Synapse

How is excitation transmitted from one neuron to another or from a neuron, for example, to a muscle fiber? This problem is of interest not only to professional neurobiologists, but also to doctors, especially pharmacologists. Knowledge of biological mechanisms is necessary for the treatment of certain diseases, as well as for the creation of new drugs and drugs. The fact is that one of the main places where these substances affect the human body are the places where excitation is transferred from one neuron to another (or to another cell, for example, a cell of the heart muscle, vascular walls, etc.). The process of a neuron axon goes to another neuron and forms a contact on it, which is called synapse(translated from Greek - contact; see Fig. 2.3). It is the synapse that holds many of the secrets of the brain. Violation of this contact, for example, by substances that block its work, leads to severe consequences for a person. This is the site of drug action. Examples will be given below, but now let's look at how the synapse is arranged and how it works.

The difficulties of this study are determined by the fact that the synapse itself is very small (its diameter is not more than 1 micron). One neuron receives such contacts, as a rule, from several thousand (3-10 thousand) other neurons. Each synapse is securely closed by special glia cells, so it is very difficult to study it. On fig. 2.12 shows a diagram of a synapse, as it is imagined modern science. Despite its diminutiveness, it is very complex. One of its main components are bubbles, that are inside the synapse. These vesicles contain a biologically very active substance called neurotransmitter or mediator(transmitter).

Recall that a nerve impulse (excitation) moves along the fiber with great speed and approaches the synapse. This action potential causes depolarization of the synapse membrane (Fig. 2.13), however, this does not lead to the generation of a new excitation (action potential), but causes the opening of special ion channels with which we are not yet familiar. These channels allow calcium ions to enter the synapse. Calcium ions play a very important role in the activity of the body. A special gland of internal secretion - parathyroid (it is located on top of the thyroid gland) regulates the calcium content in the body. Many diseases are associated with impaired calcium metabolism in the body. For example, its deficiency leads to rickets in young children.

How is calcium involved in synapse function? Once in the cytoplasm of the synaptic ending, calcium enters into contact with the proteins that form the shell of the vesicles in which the mediator is stored. Ultimately, the membranes of the synaptic vesicles contract, pushing their contents into the synaptic cleft. This process is very similar to the contraction of a muscle fiber in a muscle, in any case, these two processes have the same mechanism at the molecular level. Thus, calcium binding by the vesicle envelope proteins leads to its contraction, and the content of the vesicle is injected (exocytosis) into the gap that separates the membrane of one neuron from the membrane of another. This gap is called synoptic gap. From the description it should be clear that the excitation (electrical action potential) of a neuron at the synapse is converted from an electrical impulse into a chemical impulse. In other words, each excitation of a neuron is accompanied by the release of a portion of a biologically active substance, a mediator, at the end of its axon. Further, the mediator molecules bind to special protein molecules that are located on the membrane of another neuron. These molecules are called receptors. The receptors are unique and bind only one type of molecule. Some descriptions indicate that they fit like a "key to a lock" (a key only fits its own lock).

The receptor consists of two parts. One can be called a "recognizing center", the other - an "ion channel". If the mediator molecules have taken certain places (recognizing center) on the receptor molecule, then the ion channel opens and ions begin to enter the cell (sodium ions) or leave the cell (potassium ions). In other words, an ion current flows through the membrane, which causes a change in potential across the membrane. This potential is called postsynaptic potential(Fig. 2.13). A very important property of the described ion channels is that the number of open channels is determined by the number of bound mediator molecules, and not by the membrane potential, as is the case with the electrically excitable nerve fiber membrane. Thus, postsynaptic potentials have the property of gradation: the amplitude of the potential is determined by the number of mediator molecules bound by receptors. Due to this dependence, the amplitude of the potential on the neuron membrane develops in proportion to the number of open channels.

On the membrane of one neuron, two types of synapses can simultaneously be located: brake and excitatory. Everything is determined by the arrangement of the ion channel of the membrane. The membrane of excitatory synapses allows both sodium and potassium ions to pass through. In this case, the neuron membrane depolarizes. The membrane of inhibitory synapses allows only chloride ions to pass through and becomes hyperpolarized. Obviously, if the neuron is inhibited, the membrane potential increases (hyperpolarization). Thus, due to the action through the corresponding synapses, the neuron can be excited or stop excitation, slow down. All these events take place on the soma and numerous processes of the neuron's dendrite; on the latter, there are up to several thousand inhibitory and excitatory synapses.

As an example, let's analyze how the mediator, which is called acetylcholine. This mediator is widely distributed in the brain and in the peripheral endings of nerve fibers. For example, motor impulses, which, along the corresponding nerves, lead to the contraction of the muscles of our body, operate with acetylcholine. Acetylcholine was discovered in the 30s by the Austrian scientist O. Levy. The experiment was very simple: they isolated the heart of a frog with the vagus nerve coming to it. It was known that electrical stimulation of the vagus nerve leads to a slowdown in heart contractions up to its complete stop. O. Levy stimulated the vagus nerve, got the effect of cardiac arrest and took some blood from the heart. It turned out that if this blood is added to the ventricle of a working heart, then it slows down its contractions. It was concluded that when the vagus nerve is stimulated, a substance is released that stops the heart. It was acetylcholine. Later, an enzyme was discovered that split acetylcholine into choline (fat) and acetic acid, as a result of which the action of the mediator ceased. This study was the first to establish the exact chemical formula mediator and sequence of events in a typical chemical synapse. This sequence of events boils down to the following.

The action potential that came along the presynaptic fiber to the synapse causes depolarization, which turns on the calcium pump, and calcium ions enter the synapse; calcium ions are bound by proteins of the membrane of synaptic vesicles, which leads to active emptying (exocytosis) of the vesicles into the synaptic cleft. The mediator molecules bind (recognizing center) to the corresponding receptors of the postsynaptic membrane, and the ion channel opens. An ion current begins to flow through the membrane, which leads to the appearance of a postsynaptic potential on it. Depending on the nature of the open ion channels, an excitatory (channels for sodium and potassium ions open) or inhibitory (channels for chloride ions open) postsynaptic potential arises.

Acetylcholine is very widely distributed in wildlife. For example, it is found in the stinging capsules of nettles, in the stinging cells of intestinal animals (for example, freshwater hydra, jellyfish), etc. In our body, acetylcholine is released at the endings of the motor nerves that control muscles, from the endings of the vagus nerve, which controls the activity of the heart and other internal organs. A person has long been familiar with the antagonist of acetylcholine - it is poison curare, used by the Indians South America when hunting animals. It turned out that curare, getting into the bloodstream, causes immobilization of the animal, and it actually dies from suffocation, but curare does not stop the heart. Studies have shown that there are two types of acetylcholine receptors in the body: one successfully binds nicotinic acid, and the other is muscarine (a substance that is isolated from a fungus of the genus Muscaris). The muscles of our body have nicotinic-type receptors for acetylcholine, while the heart muscle and brain neurons have muscarinic-type acetylcholine receptors.

Currently, synthetic analogues of curare are widely used in medicine to immobilize patients during complex operations on internal organs. The use of these drugs leads to complete paralysis of the motor muscles (binding to nicotinic-type receptors), but does not affect the functioning of internal organs, including the heart (muscarinic-type receptors). Brain neurons, excited through muscarinic acetylcholine receptors, play an important role in the manifestation of certain mental functions. It is now known that the death of such neurons leads to senile dementia (Alzheimer's disease). Another example, which should show the importance of the nicotinic type receptors on the muscle for acetylcholine, is a disease called miastenia grevis (muscle weakness). This is a genetically inherited disease, i.e. its origin is associated with "breakdowns" of the genetic apparatus, which are inherited. The disease manifests itself at the age closer to puberty and begins with muscle weakness, which gradually intensifies and captures more and more extensive muscle groups. The cause of this disease turned out to be that the patient's body produces protein molecules that are perfectly bound by nicotine-type acetylcholine receptors. Occupying these receptors, they prevent the binding of acetylcholine molecules ejected from the synaptic endings of the motor nerves to them. This leads to blocking of synaptic conduction to the muscles and, consequently, to their paralysis.

The type of synaptic transmission described by the example of acetylcholine is not the only one in the CNS. The second type of synaptic transmission is also widespread, for example, in synapses, in which biogenic amines (dopamine, serotonin, adrenaline, etc.) are mediators. In this type of synapses, the following sequence of events takes place. After the complex "mediator molecule - receptor protein" is formed, a special membrane protein (G-protein) is activated. One molecule of the mediator, when bound to the receptor, can activate many G-protein molecules, and this enhances the effect of the mediator. Each activated G-protein molecule in some neurons can open an ion channel, while in others it can activate the synthesis of special molecules inside the cell, the so-called secondary intermediaries. Secondary messengers can trigger many biochemical reactions in the cell associated with the synthesis, for example, of a protein, in which case electrical potential does not occur on the neuron membrane.

There are other mediators as well. In the brain, a whole group of substances “works” as mediators, which are combined under the name biogenic amines. In the middle of the last century, the English doctor Parkinson described a disease that manifested itself as trembling paralysis. This severe suffering is caused by the destruction in the patient's brain of neurons, which in their synapses (endings) secrete dopamine - substance from the group of biogenic amines. The bodies of these neurons are located in the midbrain, forming a cluster there, which is called black substance. Research recent years showed that dopamine in the mammalian brain also has several types of receptors (six types are currently known). Another substance from the group of biogenic amines - serotonin (another name for 5-hydroxytryptamine) - was first known as a means of leading to an increase in blood pressure (vasoconstrictor). Please note that this is reflected in its name. However, it turned out that the depletion of serotonin in the brain leads to chronic insomnia. In experiments on animals, it was found that the destruction in the brain stem (posterior parts of the brain) of special nuclei, which are known in anatomy as seam core, leads to chronic insomnia and further death of these animals. Biochemical research found that the neurons of the raphe nuclei contain serotonin. In patients suffering from chronic insomnia, a decrease in the concentration of serotonin in the brain was also found.

Biogenic amines also include epinephrine and noradrenaline, which are contained in the synapses of neurons of the autonomic nervous system. During stress, under the influence of a special hormone - adrenocorticotropic (for more details, see below), adrenaline and norepinephrine are also released from the cells of the adrenal cortex into the blood.

From the above, it is clear what value in the functions nervous system mediators play. In response to the arrival of a nerve impulse to the synapse, a neurotransmitter is released; mediator molecules are connected (complementary - like a “key to a lock”) with receptors of the postsynaptic membrane, which leads to the opening of the ion channel or to the activation of intracellular reactions. The examples of synaptic transmission discussed above are fully consistent with this scheme. At the same time, thanks to research in recent decades, this rather simple scheme of chemical synaptic transmission has become much more complicated. The advent of immunochemical methods made it possible to show that several groups of mediators can coexist in one synapse, and not just one, as previously assumed. For example, synaptic vesicles containing acetylcholine and norepinephrine can simultaneously be in one synaptic ending, which are quite easily identified in electronic photographs (acetylcholine is contained in transparent vesicles with a diameter of about 50 nm, and norepinephrine is contained in electron-dense vesicles up to 200 nm in diameter). In addition to classical mediators, one or more neuropeptides may be present in the synaptic ending. The number of substances contained in the synapse can reach up to 5-6 (a kind of cocktail). Moreover, the mediator specificity of a synapse may change during ontogeny. For example, sympathetic ganglion neurons that innervate sweat glands in mammals are initially noradrenergic but become cholinergic in adult animals.

Currently, when classifying mediator substances, it is customary to distinguish: primary mediators, concomitant mediators, mediator-modulators and allosteric mediators. Primary mediators are considered to be those that act directly on the receptors of the postsynaptic membrane. Associated mediators and mediator-modulators can trigger a cascade of enzymatic reactions that, for example, phosphorylate the receptor for the primary mediator. Allosteric mediators can participate in cooperative processes of interaction with the receptors of the primary mediator.

For a long time, a synaptic transmission to an anatomical address was taken as a sample (the “point-to-point” principle). The discoveries of recent decades, especially the mediator function of neuropeptides, have shown that the principle of transmission to a chemical address is also possible in the nervous system. In other words, a mediator released from a given ending can act not only on “its own” postsynaptic membrane, but also outside this synapse - on the membranes of other neurons that have the corresponding receptors. Thus, the physiological response is provided not by the exact anatomical contact, but by the presence of the corresponding receptor on the target cell. Actually, this principle has long been known in endocrinology, and recent studies have found it more widely used.

All known types of chemoreceptors on the postsynaptic membrane are divided into two groups. One group includes receptors, which include an ion channel that opens when the mediator molecules bind to the "recognizing" center. Receptors of the second group (metabotropic receptors) open the ion channel indirectly (through a chain of biochemical reactions), in particular, through the activation of special intracellular proteins.

One of the most common are mediators belonging to the group of biogenic amines. This group of mediators is quite reliably identified by microhistological methods. Two groups of biogenic amines are known: catecholamines (dopamine, norepinephrine and adrenaline) and indolamine (serotonin). The functions of biogenic amines in the body are very diverse: mediator, hormonal, regulation of embryogenesis.

The main source of noradrenergic axons are neurons in the locus coeruleus and adjacent areas of the midbrain (Fig. 2.14). The axons of these neurons are widely distributed in the brain stem, cerebellum, and in the cerebral hemispheres. In the medulla oblongata, a large cluster of noradrenergic neurons is located in the ventrolateral nucleus of the reticular formation. In the diencephalon (hypothalamus), noradrenergic neurons, along with dopaminergic neurons, are part of the hypothalamic-pituitary system. Noradrenergic neurons are found in large numbers in the nervous peripheral system. Their bodies lie in the sympathetic chain and in some intramural ganglia.

Dopaminergic neurons in mammals are located predominantly in the midbrain (the so-called nigro-neostriatal system), as well as in the hypothalamic region. The dopamine circuits of the mammalian brain are well studied. Three main circuits are known, all of them consist of a single-neuron circuit. The bodies of neurons are in the brainstem and send axons to other areas of the brain (Fig. 2.15).

One circuit is very simple. The body of the neuron is located in the hypothalamus and sends a short axon to the pituitary gland. This pathway is part of the hypothalamic-pituitary system and controls the endocrine gland system.

The second dopamine system is also well studied. This is a black substance, many cells of which contain dopamine. The axons of these neurons project into striatum. This system contains approximately 3/4 of the dopamine in the brain. It is crucial in the regulation of tonic movements. A lack of dopamine in this system leads to Parkinson's disease. It is known that with this disease, the death of neurons of the substantia nigra occurs. The introduction of L-DOPA (a precursor of dopamine) relieves some of the symptoms of the disease in patients.

The third dopaminergic system is involved in the manifestation of schizophrenia and some other mental illnesses. The functions of this system have not yet been sufficiently studied, although the pathways themselves are well known. The bodies of neurons lie in the midbrain next to the substantia nigra. They project axons to the overlying structures of the brain, the cerebral cortex, and the limbic system, especially to the frontal cortex, the septal region, and the entorhinal cortex. The entorhinal cortex, in turn, is the main source of projections to the hippocampus.

According to the dopamine hypothesis of schizophrenia, the third dopaminergic system is overactive in this disease. These ideas arose after the discovery of substances that relieve some of the symptoms of the disease. For example, chlorpromazine and haloperidol have different chemical nature, but they equally suppress the activity of the dopaminergic system of the brain and the manifestation of some symptoms of schizophrenia. Schizophrenic patients who have been treated with these drugs for a year develop movement disorders called tardive dyskinesia (repetitive bizarre movements of the facial muscles, including the muscles of the mouth, which the patient cannot control).

Serotonin was discovered almost simultaneously as a serum vasoconstrictor factor (1948) and enteramine secreted by enterochromaffin cells of the intestinal mucosa. In 1951, the chemical structure of serotonin was deciphered and it received a new name - 5-hydroxytryptamine. In mammals, it is formed by hydroxylation of the amino acid tryptophan followed by decarboxylation. 90% of serotonin is formed in the body by enterochromaffin cells of the mucous membrane of the entire digestive tract. Intracellular serotonin is inactivated by monoamine oxidase contained in mitochondria. Serotonin in the extracellular space is oxidized by peruloplasmin. Most of the serotonin produced binds to platelets and is carried throughout the body through the bloodstream. The other part acts as a local hormone, contributing to the autoregulation of intestinal motility, as well as modulating epithelial secretion and absorption in the intestinal tract.

Serotonergic neurons are widely distributed in the central nervous system (Fig. 2.16). They are found in the dorsal and medial nuclei of the suture of the medulla oblongata, as well as in the midbrain and pons. Serotonergic neurons innervate vast areas of the brain, including the cerebral cortex, hippocampus, globus pallidus, amygdala, and hypothalamus. Interest in serotonin was attracted in connection with the problem of sleep. When the nuclei of the suture were destroyed, the animals suffered from insomnia. Substances that deplete the storage of serotonin in the brain had a similar effect.

The highest concentration of serotonin is found in the pineal gland. Serotonin in the pineal gland is converted to melatonin, which is involved in skin pigmentation, and also affects the activity of the female gonads in many animals. The content of both serotonin and melatonin in the pineal gland is controlled by the light-dark cycle through the sympathetic nervous system.

Another group of CNS mediators are amino acids. It has long been known that nerve tissue with its high level metabolism contains significant concentrations of a whole set of amino acids (listed in descending order): glutamic acid, glutamine, aspartic acid, gamma-aminobutyric acid (GABA).

Glutamate in the nervous tissue is formed mainly from glucose. In mammals, glutamate is highest in the telencephalon and cerebellum, where its concentration is about 2 times higher than in the brain stem and spinal cord. In the spinal cord, glutamate is unevenly distributed: in the posterior horns it is in greater concentration than in the anterior ones. Glutamate is one of the most abundant neurotransmitters in the CNS.

Postsynaptic glutamate receptors are classified according to affinity (affinity) for three exogenous agonists - quisgulate, kainate and N-methyl-D-aspartate (NMDA). Ion channels activated by quisgulate and kainate are similar to channels controlled by nicotinic receptors - they allow a mixture of cations to pass through (Na + and. K+). Stimulation of NMDA receptors has a complex activation pattern: the ion current, which is carried not only by Na + and K + , but also by Ca ++ when the receptor ion channel opens, depends on the membrane potential. The voltage-dependent nature of this channel is determined by the different degree of its blocking by Mg ++ ions, taking into account the level of the membrane potential. At a resting potential of the order of - 75 mV, Mg ++ ions, which are predominantly located in the intercellular environment, compete with Ca ++ and Na + ions for the corresponding membrane channels (Fig. 2.17). Due to the fact that the Mg ++ ion cannot pass through the pore, the channel is blocked every time a Mg ++ ion enters there. This leads to a decrease in the open channel time and membrane conductivity. If the neuron membrane is depolarized, then the number of Mg ++ ions that close the ion channel decreases and Ca ++ , Na + and ions can freely pass through the channel. K + . With rare stimulations (the resting potential changes little), the glutamatergic receptor EPSP occurs mainly due to the activation of quisgulate and kainate receptors; the contribution of NMDA receptors is insignificant. With prolonged membrane depolarization (rhythmic stimulation), the magnesium block is removed, and NMDA channels begin to conduct Ca ++, Na + and ions. K + . Ca++ ions can potentiate (strengthen) minPSP through second messengers, which can lead, for example, to a long-term increase in synaptic conductance, which lasts for hours and even days.

Of the inhibitory neurotransmitters, GABA is the most abundant in the CNS. It is synthesized from L-glutamic acid in one step by the enzyme decarboxylase, the presence of which is the limiting factor of this mediator. There are two types of GABA receptors on the postsynaptic membrane: GABA (opens channels for chloride ions) and GABA (opens channels for K + or Ca ++ depending on the type of cell). On fig. 2.18 shows a diagram of a GABA receptor. It is interesting that it contains a benzodiazepine receptor, the presence of which explains the action of the so-called small (daytime) tranquilizers (seduxen, tazepam, etc.). The termination of the action of the mediator in GABA synapses occurs according to the principle of reabsorption (mediator molecules are absorbed from the synaptic cleft into the cytoplasm of the neuron by a special mechanism). Of the GABA antagonists, bicuculin is well known. It passes well through the blood-brain barrier, has a strong effect on the body, even in small doses, causing convulsions and death. GABA is found in a number of neurons in the cerebellum (Purkinje cells, Golgi cells, basket cells), hippocampus (basket cells), olfactory bulb, and substantia nigra.

The identification of brain GABA circuits is difficult, since GABA is a common participant in metabolism in a number of body tissues. Metabolic GABA is not used as a mediator, although their molecules are chemically the same. GABA is determined by the decarboxylase enzyme. The method is based on obtaining antibodies to decarboxylase in animals (antibodies are extracted, labeled and injected into the brain, where they bind to decarboxylase).

Another known inhibitory mediator is glycine. Glycinergic neurons are found mainly in the spinal cord and medulla oblongata. It is believed that these cells act as inhibitory interneurons.

Acetylcholine is one of the first mediators studied. It is extremely widespread in the nervous peripheral system. An example is the motor neurons of the spinal cord and the neurons of the nuclei of the cranial nerves. Typically, cholinergic circuits in the brain are determined by the presence of the enzyme cholinesterase. In the brain, the bodies of cholinergic neurons are located in the nucleus of the septum, the nucleus of the diagonal bundle (Broca), and the basal nuclei. Neuroanatomists believe that these groups of neurons actually form one population of cholinergic neurons: the nucleus of the pedic brain, nucleus basalis (it is located in the basal part of the forebrain) (Fig. 2.19). The axons of the corresponding neurons are projected to the structures of the forebrain, especially in new bark and hippocampus. Both types of acetylcholine receptors (muscarinic and nicotinic) occur here, although muscarinic receptors are thought to dominate in the more rostrally located brain structures. According to recent data, it seems that the acetylcholine system plays an important role in the processes associated with higher integrative functions that require the participation of memory. For example, it has been shown that in the brains of patients who died of Alzheimer's disease, there is a massive loss of cholinergic neurons in the nucleus basalis.

Mediators (from lat. mediator - mediator) - substances through which the transfer of excitation from the nerve to the organs and from one neuron to another is carried out.

Systematic studies of chemical mediators of nerve influence (nerve impulses) began with the classical experiments of Levi (O. Loewi).

Subsequent studies confirmed the results of Levy's experiments on the heart and showed that not only in the heart, but also in other organs, the parasympathetic nerves exercise their influence through the mediator acetylcholine (see), and the sympathetic nerves - the mediator norepinephrine. It was further established that the somatic nervous system transmits its impulses to the skeletal muscles with the participation of the mediator acetylcholine.

Through mediators, nerve impulses are also transmitted from one neuron to another in the peripheral ganglia and the central nervous system.
Dale (N. Dale), based on the chemical nature of the mediator, divides the nervous system into cholinergic (with the mediator acetylcholine) and adrenergic (with the mediator norepinephrine). Cholinergic include postganglionic parasympathetic nerves, preganglionic parasympathetic and sympathetic nerves, and motor nerves of skeletal muscles; to adrenergic - most of the postganglionic sympathetic nerves. The sympathetic vasodilating and sweat gland nerves appear to be cholinergic. Both cholinergic and adrenergic neurons were found in the CNS.

Questions continue to be intensively studied: is the nervous system limited in its activity to only two chemical mediators - acetylcholine and norepinephrine; what mediators determine the development of the inhibition process. With regard to the peripheral part of the sympathetic nervous system, there is evidence that the inhibitory effect on the activity of organs is carried out through adrenaline (see), and the stimulating effect is norepinephrine. Flory (E. Florey) extracted from the CNS of mammals an inhibitory substance, which he called factor J, which possibly contains an inhibitory mediator. Factor J is found in the gray matter of the brain, in the centers associated with the correlation and integration of motor functions. It is identical to aminohydroxybutyric acid. When factor J is applied to the spinal cord, inhibition of reflex reactions develops, especially tendon reflexes are blocked.

In some synapses in invertebrates, gamma-aminobutyric acid plays the role of an inhibitory mediator.

Some authors seek to attribute the mediator function to serotonin. The concentration of serotonin is high in the hypothalamus, midbrain and gray matter of the spinal cord, lower in the cerebral hemispheres, cerebellum, dorsal and ventral roots. The distribution of serotonin in the nervous system coincides with the distribution of norepinephrine and adrenaline.

However, the presence of serotonin in parts of the nervous system devoid of nerve cells suggests that this substance is not related to mediator function.

Mediators are synthesized mainly in the neuron body, although many authors recognize the possibility of additional synthesis of mediators in axonal endings. The mediator synthesized in the body of the nerve cell is transported along the axon to its endings, where the mediator performs its main function of transmitting excitation to the effector organ. Along with the mediator, enzymes that ensure its synthesis are also transported along the axon (for example, choline acetylase, which synthesizes acetylcholine). Released in the presynaptic nerve endings, the mediator diffuses through the synaptic space to the postsynaptic membrane, on the surface of which it connects to a specific chemoreceptor substance, which has either an excitatory (depolarizing) or inhibitory (hyperpolarizing) effect on the membrane of the postsynaptic cell (see Synapse). Here, the mediator is destroyed under the influence of the corresponding enzymes. Acetylcholine is cleaved by cholinesterase, norepinephrine and adrenaline - mainly by monoamine oxidase.

Thus, these enzymes regulate the duration of the action of the mediator and the extent to which it spreads to neighboring structures.

See also Excitation, Neurohumoral regulation.

From the foregoing, it is clear what role mediators play in the functions of the nervous system. In response to the arrival of a nerve impulse to the synapse, a neurotransmitter is released; mediator molecules are connected (complementary - like a “key to a lock”) with receptors of the postsynaptic membrane, which leads to the opening of the ion channel or to the activation of intracellular reactions. The examples of synaptic transmission discussed above are fully consistent with this scheme. At the same time, thanks to research in recent decades, this rather simple scheme of chemical synaptic transmission has become much more complicated. The advent of immunochemical methods made it possible to show that several groups of mediators can coexist in one synapse, and not just one, as previously assumed. For example, synaptic vesicles containing acetylcholine and norepinephrine can simultaneously be in one synaptic ending, which are quite easily identified in electronic photographs (acetylcholine is contained in transparent vesicles with a diameter of about 50 nm, and norepinephrine is contained in electron-dense vesicles up to 200 nm in diameter). In addition to classical mediators, one or more neuropeptides may be present in the synaptic ending. The number of substances contained in the synapse can reach up to 5-6 (a kind of cocktail). Moreover, the mediator specificity of a synapse may change during ontogeny. For example, sympathetic ganglion neurons that innervate sweat glands in mammals are initially noradrenergic but become cholinergic in adult animals.

Currently, when classifying mediator substances, it is customary to distinguish: primary mediators, concomitant mediators, mediator-modulators and allosteric mediators. Primary mediators are considered to be those that act directly on the receptors of the postsynaptic membrane. Associated mediators and mediator-modulators can trigger a cascade of enzymatic reactions that, for example, phosphorylate the receptor for the primary mediator. Allosteric mediators can participate in cooperative processes of interaction with the receptors of the primary mediator.

For a long time, a synaptic transmission to an anatomical address was taken as a sample (the “point-to-point” principle). The discoveries of recent decades, especially the mediator function of neuropeptides, have shown that the principle of transmission to a chemical address is also possible in the nervous system. In other words, a mediator released from a given ending can act not only on “its own” postsynaptic membrane, but also outside this synapse - on the membranes of other neurons that have the corresponding receptors. Thus, the physiological response is provided not by the exact anatomical contact, but by the presence of the corresponding receptor on the target cell. Actually, this principle has long been known in endocrinology, and recent studies have found it more widely used.

All known types of chemoreceptors on the postsynaptic membrane are divided into two groups. One group includes receptors, which include an ion channel that opens when the mediator molecules bind to the "recognizing" center. Receptors of the second group (metabotropic receptors) open the ion channel indirectly (through a chain of biochemical reactions), in particular, through the activation of special intracellular proteins.

One of the most common are mediators belonging to the group of biogenic amines. This group of mediators is quite reliably identified by microhistological methods. Two groups of biogenic amines are known: catecholamines (dopamine, norepinephrine and adrenaline) and indolamine (serotonin). The functions of biogenic amines in the body are very diverse: mediator, hormonal, regulation of embryogenesis.

The main source of noradrenergic axons are neurons in the locus coeruleus and adjacent areas of the midbrain (Fig. 2.14). The axons of these neurons are widely distributed in the brain stem, cerebellum, and in the cerebral hemispheres. In the medulla oblongata, a large cluster of noradrenergic neurons is located in the ventrolateral nucleus of the reticular formation. In the diencephalon (hypothalamus), noradrenergic neurons, along with dopaminergic neurons, are part of the hypothalamic-pituitary system. Noradrenergic neurons are found in large numbers in the nervous peripheral system. Their bodies lie in the sympathetic chain and in some intramural ganglia.

Dopaminergic neurons in mammals are located predominantly in the midbrain (the so-called nigro-neostriatal system), as well as in the hypothalamic region. The dopamine circuits of the mammalian brain are well studied. Three main circuits are known, all of them consist of a single-neuron circuit. The bodies of neurons are in the brainstem and send axons to other areas of the brain (Fig. 2.15).

One circuit is very simple. The body of the neuron is located in the hypothalamus and sends a short axon to the pituitary gland. This pathway is part of the hypothalamic-pituitary system and controls the endocrine gland system.

The second dopamine system is also well studied. This is a black substance, many cells of which contain dopamine. The axons of these neurons project into the striatum. This system contains approximately 3/4 of the dopamine in the brain. It is crucial in the regulation of tonic movements. A lack of dopamine in this system leads to Parkinson's disease. It is known that with this disease, the death of neurons of the substantia nigra occurs. The introduction of L-DOPA (a precursor of dopamine) relieves some of the symptoms of the disease in patients.

The third dopaminergic system is involved in the manifestation of schizophrenia and some other mental illnesses. The functions of this system have not yet been sufficiently studied, although the pathways themselves are well known. The bodies of neurons lie in the midbrain next to the substantia nigra. They project axons to the overlying structures of the brain, the cerebral cortex, and the limbic system, especially to the frontal cortex, the septal region, and the entorhinal cortex. The entorhinal cortex, in turn, is the main source of projections to the hippocampus.

According to the dopamine hypothesis of schizophrenia, the third dopaminergic system is overactive in this disease. These ideas arose after the discovery of substances that relieve some of the symptoms of the disease. For example, chlorpromazine and haloperidol have different chemical nature, but they equally suppress the activity of the dopaminergic system of the brain and the manifestation of some symptoms of schizophrenia. Schizophrenic patients who have been treated with these drugs for a year develop movement disorders called tardive dyskinesia (repetitive bizarre movements of the facial muscles, including the muscles of the mouth, which the patient cannot control).

Serotonin was discovered almost simultaneously as a serum vasoconstrictor factor (1948) and enteramine secreted by enterochromaffin cells of the intestinal mucosa. In 1951, the chemical structure of serotonin was deciphered and it received a new name - 5-hydroxytryptamine. In mammals, it is formed by hydroxylation of the amino acid tryptophan followed by decarboxylation. 90% of serotonin is formed in the body by enterochromaffin cells of the mucous membrane of the entire digestive tract. Intracellular serotonin is inactivated by monoamine oxidase contained in mitochondria. Serotonin in the extracellular space is oxidized by peruloplasmin. Most of the serotonin produced binds to platelets and is carried throughout the body through the bloodstream. The other part acts as a local hormone, contributing to the autoregulation of intestinal motility, as well as modulating epithelial secretion and absorption in the intestinal tract.

Serotonergic neurons are widely distributed in the central nervous system (Fig. 2.16). They are found in the dorsal and medial nuclei of the suture of the medulla oblongata, as well as in the midbrain and pons. Serotonergic neurons innervate vast areas of the brain, including the cerebral cortex, hippocampus, globus pallidus, amygdala, and hypothalamus. Interest in serotonin was attracted in connection with the problem of sleep. When the nuclei of the suture were destroyed, the animals suffered from insomnia. Substances that deplete the storage of serotonin in the brain had a similar effect.

The highest concentration of serotonin is found in the pineal gland. Serotonin in the pineal gland is converted to melatonin, which is involved in skin pigmentation, and also affects the activity of the female gonads in many animals. The content of both serotonin and melatonin in the pineal gland is controlled by the light-dark cycle through the sympathetic nervous system.

Another group of CNS mediators are amino acids. It has long been known that nervous tissue, with its high metabolic rate, contains significant concentrations of a whole range of amino acids (listed in descending order): glutamic acid, glutamine, aspartic acid, gamma-aminobutyric acid (GABA).

Glutamate in the nervous tissue is formed mainly from glucose. In mammals, glutamate is highest in the telencephalon and cerebellum, where its concentration is about 2 times higher than in the brain stem and spinal cord. In the spinal cord, glutamate is unevenly distributed: in the posterior horns it is in greater concentration than in the anterior ones. Glutamate is one of the most abundant neurotransmitters in the CNS.

Postsynaptic glutamate receptors are classified according to affinity (affinity) for three exogenous agonists - quisgulate, kainate and N-methyl-D-aspartate (NMDA). Ion channels activated by quisgulate and kainate are similar to channels controlled by nicotinic receptors - they allow a mixture of cations to pass through (Na + and. K+). Stimulation of NMDA receptors has a complex activation pattern: the ion current, which is carried not only by Na + and K + , but also by Ca ++ when the receptor ion channel opens, depends on the membrane potential. The voltage-dependent nature of this channel is determined by the different degree of its blocking by Mg ++ ions, taking into account the level of the membrane potential. At a resting potential of the order of - 75 mV, Mg ++ ions, which are predominantly located in the intercellular environment, compete with Ca ++ and Na + ions for the corresponding membrane channels (Fig. 2.17). Due to the fact that the Mg ++ ion cannot pass through the pore, the channel is blocked every time a Mg ++ ion enters it. This leads to a decrease in the open channel time and membrane conductivity. If the neuron membrane is depolarized, then the number of Mg ++ ions that close the ion channel decreases and Ca ++ , Na + and ions can freely pass through the channel. K + . With rare stimulations (the resting potential changes little), the glutamatergic receptor EPSP occurs mainly due to the activation of quisgulate and kainate receptors; the contribution of NMDA receptors is insignificant. With prolonged membrane depolarization (rhythmic stimulation), the magnesium block is removed, and the NMDA channels begin to conduct Ca ++, Na + and ions. K + . Ca++ ions can potentiate (strengthen) minPSP through second messengers, which can lead, for example, to a long-term increase in synaptic conductance, which lasts for hours and even days.

Of the inhibitory neurotransmitters, GABA is the most abundant in the CNS. It is synthesized from L-glutamic acid in one step by the enzyme decarboxylase, the presence of which is the limiting factor of this mediator. There are two types of GABA receptors on the postsynaptic membrane: GABA (opens channels for chloride ions) and GABA (opens channels for K + or Ca ++ depending on the type of cell). On fig. 2.18 shows a diagram of a GABA receptor. It is interesting that it contains a benzodiazepine receptor, the presence of which explains the action of the so-called small (daytime) tranquilizers (seduxen, tazepam, etc.). The termination of the action of the mediator in GABA synapses occurs according to the principle of reabsorption (mediator molecules are absorbed from the synaptic cleft into the cytoplasm of the neuron by a special mechanism). Of the GABA antagonists, bicuculin is well known. It passes well through the blood-brain barrier, has a strong effect on the body, even in small doses, causing convulsions and death. GABA is found in a number of neurons in the cerebellum (Purkinje cells, Golgi cells, basket cells), hippocampus (basket cells), olfactory bulb, and substantia nigra.

The identification of brain GABA circuits is difficult, since GABA is a common participant in metabolism in a number of body tissues. Metabolic GABA is not used as a mediator, although their molecules are chemically the same. GABA is determined by the decarboxylase enzyme. The method is based on obtaining antibodies to decarboxylase in animals (antibodies are extracted, labeled and injected into the brain, where they bind to decarboxylase).

Another known inhibitory mediator is glycine. Glycinergic neurons are found mainly in the spinal cord and medulla oblongata. It is believed that these cells act as inhibitory interneurons.

Acetylcholine is one of the first mediators studied. It is extremely widespread in the nervous peripheral system. An example is the motor neurons of the spinal cord and the neurons of the nuclei of the cranial nerves. Typically, cholinergic circuits in the brain are determined by the presence of the enzyme cholinesterase. In the brain, the bodies of cholinergic neurons are located in the nucleus of the septum, the nucleus of the diagonal bundle (Broca), and the basal nuclei. Neuroanatomists believe that these groups of neurons actually form one population of cholinergic neurons: the nucleus of the pedic brain, nucleus basalis (it is located in the basal part of the forebrain) (Fig. 2.19). The axons of the corresponding neurons project to the structures of the forebrain, especially the neocortex and the hippocampus. Both types of acetylcholine receptors (muscarinic and nicotinic) occur here, although muscarinic receptors are thought to dominate in the more rostrally located brain structures. According to recent data, it seems that the acetylcholine system plays an important role in the processes associated with higher integrative functions that require the participation of memory. For example, it has been shown that in the brains of patients who died of Alzheimer's disease, there is a massive loss of cholinergic neurons in the nucleus basalis.

Mediator - See Mediator. * * * (lat. mediator - mediator) - a biologically active substance involved in the transfer of excitation from one nerve cell to another through a synapse (see) or from a neuron to an executive organ (muscle, gland, etc.).

Mediators - active chemicals that cause the transmission of excitation in the synapse (see). Mediators in the form of small vesicles (vesicles) accumulate on the presynaptic membrane. Under the influence of a nerve impulse, the vesicles burst and their contents are poured into the synaptic cleft. Acting on the postsynaptic membrane, mediators cause its depolarization (see Excitation). The mediators most studied and widespread in an organism are acetylcholine (see) and norepinephrine. In accordance with this, all nerve endings that transmit excitations to various organs are divided into cholinergic, where the mediators of synaptic transmission are acetylcholine, and adrenergic, in which norepinephrine serves as a mediator. Cholinergic fibers include somatic nervous system fibers that transmit excitation to skeletal muscles, preganglionic fibers of the sympathetic and parasympathetic systems, and postganglionic parasympathetic fibers. Postganglionic sympathetic fibers are predominantly adrenergic. There are synapses in the central nervous system that use both acetylcholine and norepinephrine as a mediator, as well as serotonin, gamma-aminobutyric acid, L-glutamate, and some other amino acids.

A synapse is a place of contact between two cell membranes, which ensures the transfer of excitation from nerve endings to excitable structures (glands, muscles, neurons). Depending on the structure, synapses are divided into neurosecretory, neuromuscular, interneuronal. The synapse consists of 2 membranes: presynaptic, which is part of the nerve ending, and postsynaptic, belonging to the excitable structure.

Transfer of excitement in a synapse is carried out by means of specific chemicals - mediators (see). The most common mediators are norepinephrine and acetylcholine. The structure of the synapse and the mechanism of transmission of excitation determine its physiological properties: 1) unilateral conduction of excitation associated with the release of the mediator only on the presynaptic membrane; 2) synaptic delay in the transmission of excitation associated with the slow release of the mediator and its effect on the postsynaptic membrane, it can be shortened with repeated passage of excitation (the effect of summation and facilitation); 3) the synapse has low lability and easy fatigability; 4) the chemical mechanism of excitation transmission in the synapse determines the high sensitivity of the synapse to hormones, drugs and poisons.

Question 26. Types and role of central nervous inhibition.

Inhibition is a local nervous process leading to inhibition or prevention of excitation. Inhibition is an active nervous process, the result of which is the limitation or delay of excitation. One of the characteristic features of the inhibitory process is the lack of the ability to actively spread through the nervous structures.

Currently, two types of inhibition are distinguished in the central nervous system: central (primary) inhibition, which is the result of excitation (activation) of special inhibitory neurons, and secondary inhibition, which is carried out without the participation of special inhibitory structures in the very neurons in which excitation occurs.

Central inhibition (primary) is a nervous process that occurs in the central nervous system and leads to the weakening or prevention of excitation. According to modern concepts, central inhibition is associated with the action of inhibitory neurons or synapses that produce inhibitory mediators (glycine, gamma-aminobutyric acid), which cause a special type of electrical changes on the postsynaptic membrane called inhibitory postsynaptic potentials (IPSP) or depolarization of the presynaptic nerve ending with which another nerve ending of the axon. Therefore, central (primary) postsynaptic inhibition and central (primary) presynaptic inhibition are distinguished.

Post-synaptic inhibition (Latin post behind, after something + Greek sinapsis contact, connection) is a nervous process caused by the action on the postsynaptic membrane of specific inhibitory mediators (glycine, gamma-aminobutyric acid) secreted by specialized presynaptic nerve endings. The mediator secreted by them changes the properties of the postsynaptic membrane, which causes suppression of the cell's ability to generate excitation. In this case, a short-term increase in the permeability of the postsynaptic membrane to K+ or CI- ions occurs, causing a decrease in its input electrical resistance and the generation of an inhibitory postsynaptic potential (IPSP). The occurrence of IPSP in response to afferent stimulation is necessarily associated with the inclusion of an additional link in the inhibitory process - an inhibitory interneuron, the axonal endings of which release an inhibitory neurotransmitter. The specificity of inhibitory postsynaptic effects was first studied in mammalian motor neurons (D. Eccles, 1951). Subsequently, primary IPSPs were recorded in interneurons of the spinal and medulla oblongata, in neurons of the reticular formation, cerebral cortex, cerebellum, and thalamic nuclei of warm-blooded animals.

It is known that when the center of the flexors of one of the limbs is excited, the center of its extensors is inhibited and vice versa. D. Eccles found out the mechanism of this phenomenon in the following experiment. He irritated the afferent nerve, causing excitation of the motor neuron that innervates the extensor muscle.

Nerve impulses, having reached the afferent neuron in the spinal ganglion, are sent along its axon in the spinal cord in two ways: to the motor neuron that innervates the extensor muscle, exciting it, and along the collaters to the intermediate inhibitory neuron, the axon of which contacts the motor neuron that innervates the flexor muscle, thus causing inhibition of the antagonistic muscle. This type of inhibition was found in intermediate neurons of all levels of the central nervous system during the interaction of antagonistic centers. It has been called translational postsynaptic inhibition. This type of inhibition coordinates and distributes the processes of excitation and inhibition between the nerve centers.

Reverse (antidromic) postsynaptic inhibition (Greek: antidromeo to run in the opposite direction) is the process of regulation by nerve cells of the intensity of the signals coming to them according to the principle of negative feedback. It lies in the fact that the axon collaterals of the nerve cell establish synaptic contacts with special intercalary neurons (Renshaw cells), the role of which is to influence the neurons that converge on the cell that sends these axon collaterals (Fig. 87). According to this principle, the inhibition of motor neurons is carried out.

The appearance of an impulse in a mammalian motor neuron not only activates muscle fibers, but also activates inhibitory Renshaw cells through axon collaterals. The latter establish synaptic connections with motor neurons. Therefore, an increase in motor neuron firing leads to greater activation of Renshaw cells, which causes increased inhibition of motor neurons and a decrease in the frequency of their firing. The term "antidromic" is used because the inhibitory effect is easily caused by antidromic impulses reflexively occurring in motor neurons.

The stronger the motor neuron is excited, the more strong impulses go to the skeletal muscles along its axon, the more intensely the Renshaw cell is excited, which suppresses the activity of the motor neuron. Therefore, there is a mechanism in the nervous system that protects neurons from excessive excitation. A characteristic feature of postsynaptic inhibition is that it is suppressed by strychnine and tetanus toxin (these pharmacological substances do not act on excitation processes).

As a result of the suppression of postsynaptic inhibition, the regulation of excitation in the central nervous system is disturbed, the excitation spills (“diffuses”) throughout the central nervous system, causing overexcitation of motor neurons and convulsive contractions of muscle groups (convulsions).

Reticular inhibition (lat. reticularis - net) is a nervous process developing in spinal neurons under the influence of descending impulses from the reticular formation (giant reticular nucleus of the medulla oblongata). The effects created by reticular influences are functionally similar to the recurrent inhibition that develops on motor neurons. The influence of the reticular formation is caused by persistent IPSP, covering all motor neurons, regardless of their functional affiliation. In this case, as in the case of recurrent inhibition of motor neurons, their activity is limited. Between such downward control from the reticular formation and the system of recurrent inhibition through Renshaw cells, there is a certain interaction, and Renshaw cells are under constant inhibitory control from the two structures. The inhibitory influence from the reticular formation is an additional factor in the regulation of the level of motor neuron activity.

Primary inhibition can be caused by mechanisms of a different nature, not associated with changes in the properties of the postsynaptic membrane. Inhibition in this case occurs on the presynaptic membrane (synaptic and presynaptic inhibition).

Synaptic inhibition (Greek sunapsis contact, connection) is a nervous process based on the interaction of a mediator secreted and released by presynaptic nerve endings with specific molecules of the postsynaptic membrane. The excitatory or inhibitory nature of the action of the mediator depends on the nature of the channels that open in the postsynaptic membrane. Direct proof of the presence of specific inhibitory synapses in the CNS was first obtained by D. Lloyd (1941).

Data regarding the electrophysiological manifestations of synaptic inhibition: the presence of synaptic delay, the absence electric field in the area of ​​synaptic endings, they gave reason to consider it a consequence of the chemical action of a special inhibitory mediator secreted by synaptic endings. D. Lloyd showed that if the cell is in a state of depolarization, then the inhibitory mediator causes hyperpolarization, while against the background of hyperpolarization of the postsynaptic membrane, it causes its depolarization.

Presynaptic inhibition (Latin prae - ahead of something + Greek sunapsis contact, connection) - special case synaptic inhibitory processes, manifested in the suppression of neuron activity as a result of a decrease in the effectiveness of excitatory synapses even at the presynaptic link by inhibiting the release of the mediator by excitatory nerve endings. In this case, the properties of the postsynaptic membrane do not undergo any changes. Presynaptic inhibition is carried out by means of special inhibitory interneurons. Its structural basis is axo-axonal synapses formed by axon terminals of inhibitory interneurons and axonal endings of excitatory neurons.

In this case, the axon ending of the inhibitory neuron is presympathetic with respect to the terminal of the excitatory neuron, which is postsynaptic with respect to the inhibitory ending and presynaptic with respect to the nerve cell activated by it. In the endings of the presynaptic inhibitory axon, a mediator is released, which causes depolarization of excitatory endings by increasing the permeability of their membrane for CI-. Depolarization causes a decrease in the amplitude of the action potential arriving at the excitatory ending of the axon. As a result, the mediator release process is inhibited by excitatory nerve endings and the amplitude of the excitatory postsynaptic potential decreases.

A characteristic feature of presynaptic depolarization is slow development and long duration (several hundred milliseconds), even after a single afferent impulse.

Presynaptic inhibition differs significantly from postsynaptic inhibition in pharmacological terms as well. Strychnine and tetanus toxin do not affect its course. However, narcotic substances (chloralose, nembutal) significantly enhance and lengthen presynaptic inhibition. This type of inhibition is found in various parts of the central nervous system. Most often it is detected in the structures of the brain stem and spinal cord. In the first studies of the mechanisms of presynaptic inhibition, it was believed that the inhibitory action is carried out at a point remote from the soma of the neuron, therefore it was called "remote" inhibition.

The functional significance of presynaptic inhibition, covering the presynaptic terminals through which afferent impulses arrive, is to limit the flow of afferent impulses to the nerve centers. Presynaptic inhibition primarily blocks weak asynchronous afferent signals and passes stronger ones, therefore, it serves as a mechanism for isolating, isolating more intense afferent impulses from the general flow. This is of great adaptive importance for the organism, since of all the afferent signals going to the nerve centers, the most important, the most necessary for this particular time, stand out. Thanks to this, the nerve centers, the nervous system as a whole, are freed from the processing of less essential information.

Secondary inhibition - inhibition carried out by the same nerve structures in which excitation occurs. This nervous process is described in detail in the works of N.E. Vvedensky (1886, 1901).

Reciprocal inhibition (Latin reciprocus - mutual) is a nervous process based on the fact that the same afferent pathways through which the excitation of one group of nerve cells is carried out provide inhibition of other groups of cells through intercalary neurons. Reciprocal relations of excitation and inhibition in the central nervous system were discovered and demonstrated by N.E. Vvedensky: irritation of the skin on the hind leg in a frog causes its flexion and inhibition of flexion or extension on the opposite side. The interaction of excitation and inhibition is a common property of the entire nervous system and is found both in the brain and in the spinal cord. It has been experimentally proven that the normal performance of each natural motor act is based on the interaction of excitation and inhibition on the same CNS neurons.

General central inhibition is a nervous process that develops with any reflex activity and captures almost the entire central nervous system, including the centers of the brain. General central inhibition usually manifests itself before the occurrence of any motor reaction. It can manifest itself with such a small force of irritation at which there is no motor effect. This type of inhibition was first described by I.S. Beritov (1937). It provides a concentration of excitation of other reflex or behavioral acts that could arise under the influence of stimuli. An important role in the creation of general central inhibition belongs to the gelatinous substance of the spinal cord.

With electrical stimulation of the gelatinous substance in the spinal preparation of a cat, a general inhibition of reflex reactions caused by irritation of the sensory nerves occurs. General inhibition is an important factor in creating an integral behavioral activity of animals, as well as in ensuring selective excitation of certain working organs.

Parabiotic inhibition develops in pathological conditions, when the lability of the structures of the central nervous system decreases or there is a very massive simultaneous excitation of a large number of afferent pathways, as, for example, in traumatic shock.

Some researchers distinguish another type of inhibition - inhibition following excitation. It develops in neurons after the end of excitation as a result of a strong trace hyperpolarization of the membrane (postsynaptic).

Inhibition is a special nervous process, which is caused by excitation and is outwardly manifested by the inhibition of another excitation. It is able to actively spread by the nerve cell and its processes. The theory of central inhibition was founded by IM Sechenov (1863), who noticed that the frog's bending reflex is inhibited by chemical stimulation of the midbrain. Inhibition plays an important role in the activity of the central nervous system, namely: in the coordination of reflexes; in human and animal behavior; in the regulation of the activity of internal organs and systems; in the implementation of the protective function of nerve cells.

Types of inhibition in the CNS

Central inhibition is distributed according to localization into pre- and postsynaptic;

by the nature of polarization (membrane charge) - on hyper- and depolarization;

according to the structure of inhibitory neural circuits - into reciprocal, or connected, reverse and lateral.

Presynaptic inhibition, as the name suggests, is localized in presynaptic elements and is associated with inhibition of nerve impulse conduction in axonal (presynaptic) endings. The histological substrate of such inhibition is axonal synapses. An insertion inhibitory axon approaches the excitatory axon and releases the inhibitory neurotransmitter GABA. This mediator acts on the postsynaptic membrane, which is the membrane of the excitatory axon, and causes depolarization in it. The resulting depolarization inhibits the entry of Ca2 + from the synaptic cleft into the conclusion of the excitatory axon and thus leads to a decrease in the release of the excitatory mediator into the synaptic cleft, inhibition of the reaction. Presynaptic inhibition reaches a maximum after 15-20 ms and lasts about 150 ms, that is, much longer than postsynaptic inhibition. Presynaptic inhibition is blocked by convulsive poisons - biculin and picrotoxin, which are competitive GABA antagonists.

Postsynaptic inhibition (GPSP) is caused by the release of an inhibitory mediator by the presynaptic ending of the axon, which reduces or inhibits the excitability of the membranes of the soma and dendrites of the nerve cell with which it contacts. It is associated with the existence of inhibitory neurons, the axons of which form on the soma and dendrites of the cells of nerve endings, releasing inhibitory mediators - GABA and glycine. Under the influence of these mediators, inhibition of excitatory neurons occurs. Examples of inhibitory neurons are Renshaw cells in the spinal cord, pear-shaped neurons (Purkinje cells of the cerebellum), stellate cells of the cerebral cortex, brain, etc.

A study by P. G. Kostyuk (1977) proved that postsynaptic inhibition is associated with primary hyperpolarization of the membrane of the soma of the neuron, which is based on an increase in the permeability of the postsynaptic membrane for K +. As a result of hyperpolarization, the level of the membrane potential moves away from the critical (threshold) level. That is, its increase occurs - hyperpolarization. This leads to the inhibition of the neuron. This type of inhibition is called hyperpolarization.

The amplitude and polarity of the HPSP depend on the initial level of the membrane potential of the neuron itself. The mechanism of this phenomenon is associated with Cl+. With the onset of IPSP development, Cl- enters the cell. When there is more of it inside the cell than outside, glycine conforms to the membrane and Cl+ exits the cell through its open holes. It reduces the number of negative charges, depolarization develops. This type of inhibition is called depolarization.

Postsynaptic inhibition is local. It develops gradually, capable of summation, leaving no refractoriness behind. It is a more responsive, well-targeted and versatile braking mechanism. At its core, this is "central inhibition", which was described at the time by Ch. S. Sherrington (1906).

Depending on the structure of the inhibitory neuronal chain, the following forms of postsynaptic inhibition are distinguished: reciprocal, reverse and lateral, which is actually a kind of reverse.

Reciprocal (combined) inhibition is characterized by the fact that when, for example, motor neurons of flexor muscles are excited during activation of afferents, then simultaneously (on this side) motor neurons of extensor muscles acting on the same joint are inhibited. This happens because afferents from the muscle spindles form excitatory synapses on the motor neurons of the agonist muscles, and through the intervening inhibitory neuron, inhibitory synapses on the motor neurons of the antagonist muscles. From a physiological point of view, such inhibition is very beneficial, since it facilitates the movement of the joint “automatically”, without additional voluntary or involuntary control.

Reverse braking. In this case, one or more collaterals depart from the axons of the motor neuron, which are directed to the insertion inhibitory neurons, for example, Renshaw cells. In turn, Renshaw cells form inhibitory synapses on motor neurons. In the case of excitation of the motor neuron, Renshaw cells are also activated, as a result of which hyperpolarization of the motor neuron membrane occurs and its activity is inhibited. The more the motor neuron is excited, the greater the tangible inhibitory effects through Renshaw cells. Thus, reverse postsynaptic inhibition functions on the principle of negative feedback. There is an assumption that this type of inhibition is required for self-regulation of excitation of neurons, as well as to prevent their overexcitation and convulsive reactions.

Lateral inhibition. The inhibitory chain of neurons is characterized by the fact that inhibitory neurons affect not only the inflamed cell, but also neighboring neurons, in which excitation is weak or completely absent. Such inhibition is called lateral, since the site of inhibition that is formed is contained laterally (laterally) from the excited neuron. It plays a particularly important role in sensory systems, creating the phenomenon of contrast.

Postsynaptic inhibition is predominantly easily removed by the introduction of strychnine, which competes with the inhibitory mediator (glycine) on the postsynaptic membrane. Tetanus toxin also inhibits postsynaptic inhibition by interfering with neurotransmitter release from inhibitory presynaptic endings. Therefore, the introduction of strychnine or tetanus toxin is accompanied by convulsions that occur as a result of a sharp increase in the excitation process in the central nervous system, in particular, motor neurons.

In connection with the discovery of the ionic mechanisms of postsynaptic inhibition, it became possible to explain the mechanism of action of Br. Sodium bromide in optimal doses is widely used in clinical practice as a sedative (sedative) agent. It has been proven that this effect of sodium bromide is associated with increased postsynaptic inhibition in the CNS. -

The role of various types of central inhibition

The main role of central inhibition is to provide, in interaction with central excitation, the possibility of analyzing and synthesizing nerve signals in the central nervous system, and, consequently, the possibility of coordinating all body functions with each other and with the environment. This role of central inhibition is called coordination. Some types of central inhibition perform not only a coordinating, but also a protective (guard) role. It is assumed that the main coordinating role of presynaptic inhibition is the suppression in the CNS by insignificant afferent signals. Due to direct postsynaptic inhibition, the activity of antagonistic centers is coordinated. Reverse inhibition, limiting the maximum possible frequency of discharges of motoneurons of the spinal cord, performs both a coordinating role (coordinates the maximum frequency of motoneuron discharges with the rate of contraction of the muscle fibers that they innervate) and protective (prevents the excitation of motoneurons). In mammals, this type of inhibition is distributed mainly in the spinal afferent systems. In the higher parts of the brain, namely in the cortex big brain dominated by postsynaptic inhibition.

What is the functional significance of presynaptic inhibition? Due to it, the impact is carried out not only on the own reflex apparatus of the spinal cord, but also on the synaptic switching of a number of tracts ascending through the brain. It is also known about the descending presynaptic inhibition of the primary afferent fibers of the Aa group and skin afferents. In this case, presynaptic inhibition is obviously the first "tier" of active restriction of information coming from outside. In the CNS, especially in the spinal cord, presynaptic inhibition often acts as a kind of negative feedback that limits afferent impulses during strong (for example, pathological) stimuli and thus partly performs a protective function in relation to the spinal cord and higher located centers.

The functional properties of synapses are not constant. Under certain conditions, the effectiveness of their activities may increase or decrease. Usually, at high frequencies of stimulation (several hundred per 1 s), synaptic transmission is facilitated within a few seconds or even minutes. This phenomenon is called synaptic potentiation. Such synaptic potentiation can also be observed after the end of tetanic stimulation. Then it will be called post-tetanic potentiation (PTP). At the heart of PTP (long-term increase in the efficiency of communication between neurons), it is likely that there are changes in the functionality of the presynaptic fiber, namely its hyperpolarization. In turn, this is accompanied by an increase in the release of the neurotransmitter into the synaptic cleft and the appearance of an increased EPSP in the postsynaptic structure. There are also data on structural changes in PTP (swelling and growth of presynaptic endings, narrowing of the synaptic gap, etc.).

PTP is much better expressed in the higher parts of the CNS (for example, in the hippocampus, pyramidal neurons of the cerebral cortex) compared to spinal neurons. Along with PTP, post-activation depression may occur in the synaptic apparatus, which is expressed by a decrease in the amplitude of EPSP. This depression is associated by many researchers with a weakening of the sensitivity to the action of the mediator (desensitization) of the postsynaptic membrane or a different ratio of costs and mobilization of the mediator.

The plasticity of synaptic processes, in particular, PTP, may be associated with the formation of new interneuronal connections in the CNS and their fixation, i.e. mechanisms of learning and memory. At the same time, it should be recognized that the plastic properties of central synapses have not yet been sufficiently studied.

According to the chemical structure, mediators are a heterogeneous group. It includes choline ester (acetylcholine); a group of monoamines, including catecholamines (dopamine, norepinephrine and epinephrine); indoles (serotonin) and imidazoles (histamine); acidic (glutamate and aspartate) and basic (GABA and glycine) amino acids; purines (adenosine, ATP) and peptides (enkephalins, endorphins, substance P). This group also includes substances that cannot be classified as true neurotransmitters - steroids, eicosanoids and a number of ROS, primarily NO.

A number of criteria are used to decide on the neurotransmitter nature of a compound. The main ones are listed below.

1. The substance must accumulate in presynaptic endings and be released in response to an incoming impulse. The presynaptic region must contain the system for the synthesis of this substance, and the postsynaptic zone must detect a specific receptor for this compound.
2. When the presynaptic region is stimulated, Ca-dependent release (by exocytosis) of this compound into the intersynaptic cleft, proportional to the strength of the stimulus, should occur.
3. Mandatory identity of the effects of the endogenous neurotransmitter and the putative mediator when it is applied to the target cell and the possibility of pharmacological blocking of the effects of the putative mediator.
4. The presence of a reuptake system of the putative mediator into presynaptic terminals and/or into neighboring astroglial cells. There may be cases when not the mediator itself, but the product of its cleavage is subjected to reuptake (for example, choline after the cleavage of acetylcholine by the enzyme acetylcholinesterase).

Influence of drugs on various stages of mediator function in synaptic transmission

The use of various methods for testing the mediator function, including the most modern ones (immunohistochemical, recombinant DNA, etc.), is difficult due to the limited availability of most individual synapses, as well as due to the limited set of targeted pharmacological agents.

An attempt to define the concept of "mediators" encounters a number of difficulties, since in recent decades the list of substances that perform the same signaling function in the nervous system as classical mediators, but differ from them in chemical nature, synthesis pathways, receptors, has significantly expanded. First of all, the above applies to a large group of neuropeptides, as well as to ROS, and primarily to nitric oxide (nitroxide, NO), for which the mediator properties are well described. Unlike "classical" mediators, neuropeptides are usually larger, synthesized at a low rate, accumulate in low concentrations, and bind to receptors with low specific affinity; in addition, they do not have presynaptic terminal reuptake mechanisms. The duration of the effect of neuropeptides and mediators also varies significantly. As for nitroxide, despite its participation in intercellular interaction, according to a number of criteria, it can be attributed not to mediators, but to secondary messengers.

Initially, it was thought that a nerve ending could contain only one neurotransmitter. To date, the possibility of the presence in the terminal of several mediators released jointly in response to an impulse and acting on one target cell - concomitant (coexisting) mediators (commediators, cotransmitters) has been shown. In this case, the accumulation of different mediators occurs in the same presynaptic region, but in different vesicles. Examples of mediators are classical neurotransmitters and neuropeptides, which differ in the place of synthesis and, as a rule, are localized in one end. The release of cotransmitters occurs in response to a series of excitatory potentials of a certain frequency.

In modern neurochemistry, in addition to neurotransmitters, substances are isolated that modulate their effects - neuromodulators. Their action is tonic in nature and longer in time than the action of mediators. These substances can have not only neuronal (synaptic) but also glial origin and are not necessarily mediated by nerve impulses. Unlike a neurotransmitter, a modulator acts not only on the postsynaptic membrane, but also on other parts of the neuron, including intracellularly.

There are pre- and postsynaptic modulation. The concept of "neuromodulator" is broader than the concept of "neurotransmitter". In some cases, the mediator may also be a modulator. For example, norepinephrine, released from the sympathetic nerve ending, acts as a neurotransmitter on a1 receptors, but as a neuromodulator on a2 adrenergic receptors; in the latter case, it mediates inhibition of the subsequent secretion of norepinephrine.

Substances that perform mediator functions differ not only in their chemical structure, but also in which compartments of the nerve cell they are synthesized. Classical small molecule mediators are synthesized in the axon terminal and are incorporated into small synaptic vesicles (50 nm in diameter) for storage and release. NO is also synthesized in the terminal, but since it cannot be packaged in vesicles, it immediately diffuses out of the nerve ending and affects the target. Peptide neurotransmitters are synthesized in the central part of the neuron (perikaryon), packed into large vesicles with a dense center (100-200 nm in diameter) and transported by axonal current to the nerve endings.

Acetylcholine and catecholamines are synthesized from circulating precursors, while amino acid mediators and peptides are ultimately formed from glucose. As is known, neurons (like other cells of higher animals and humans) cannot synthesize tryptophan. Therefore, the first step leading to the beginning of the synthesis of serotonin is the facilitated transport of tryptophan from the blood to the brain. This amino acid, like other neutral amino acids (phenylalanine, leucine and methionine), is transported from the blood to the brain by special carriers belonging to the family of monocarboxylic acid carriers. Thus, one of important factors that determine the level of serotonin in serotonergic neurons is the relative amount of tryptophan in food compared to other neutral amino acids. For example, volunteers who were fed a low-protein diet for one day and then given a tryptophan-free amino acid mixture exhibited aggressive behavior and altered sleep-wake cycles associated with decreased levels of serotonin in the brain.