CENTRAL NERVOUS SYSTEM SYNAPSES

PHYSIOLOGY OF SYNAPSES. INTERNEURONAL CONNECTIONS

Every medical student is aware that information is transmitted in the central nervous system mainly in the form of nerve action potentials, called simply "nerve impulses," through a succession of neurons, one after another. However, in addition, each impulse may be blocked in its transmission from one neuron to the next, may be changed from a single impulse into repetitive impulses, or may be integrated with impulses from other neurons to cause highly intricate patterns of impulses in successive neurons. All these functions can be classified as synoptic functions of neurons.

Common characteristic of synaptic and junction transmission (Impulses are transmitted from one nerve cell to another at synapses. These are the junctions where the axon or some other portion of one cell (the presynaptic cell) terminates on the soma, the dendrites, or some other portion of another neuron (the postsynaptic cell). It is worth noting that dendrites as well as axons can be presynaptic or postsynaptic. Transmission at most of the junctions is chemical; the impulse in the presynaptic axon liberates a chemical mediator. The chemical mediator binds to receptors on the surface of the postsynaptic cell, and this triggers intracellular events that alter the permeability of the membrane of the postsynaptic neuron. At some of the junctions, however, transmission is electrical, and at a few conjoint synapses it is both electrical and chemical. In any case, impulses in the presynaptic fibers usually contribute to the initiation of conducted responses in the postsynaptic cell, but transmission is not a simple jumping of one action potential from the presynaptic to the postsynaptic neuron. It is a complex process that permits the grading and modulation of neural activity necessary for normal function.

In the case of electrical synapses, the membranes of the presynaptic and postsynaptic neurons come close together, forming a gap junction. Like the intercellular junctions in other tissues, these junctions form low-resistance bridges through which ions pass with relative ease. Electrical and conjoint synapses occur in mammals, and there is electrical coupling, for example, between some of the neurons in the lateral vestibular nucleus. However, most synaptic transmission is chemical.

Transmission from nerve to muscle resembles chemical synaptic transmission. The myoneural junction, the specialized area where a motor nerve terminates on a skeletal muscle fiber, is the site of a stereotyped transmission process. The contacts between autonomic neurons and smooth and cardiac muscle are less specialized, and transmission is a more diffuse process.)

a) Classification of synapses (For localization – central (neuro-neuronal) and peripheral (neuro-muscles, neuro-secretion; central synapses may be axo-somatic, axo-dendrites, axo-axonal, dendro-dendrites; for functional meaning – excitatory and inhibitory; for the method of transmission – electrical and chemical.

There is considerable variation in the anatomic structure of synapses in various parts of the mammalian nervous system. The ends of the presynaptic fibers are generally enlarged to form terminal buttons (synaptic knobs). Endings are commonly located on dendritic spines, which are small knobs projecting from dendrites. In some instances, the terminal branches of the axon of the presynaptic neuron form a basket or net around the soma of the postsynaptic cell (“basket cells” of the cerebellum and autonomic ganglia). In other locations, they intertwine with the dendrites of the postsynaptic cell (climbing fibers of the cerebellum) or end on the dendrites directly (apical dendrites of cortical pyramids) or on the axons (axo-axonal endings). In the spinal cord, the presynaptic endings are closely applied to the soma and the proximal portions of the dendrites of the postsynaptic neuron. The number of synaptic knobs varies from one per postsynaptic cell (in the midbrain) to a very large number. The number of synaptic knobs applied to a single spinal motor neuron has been calculated to be about 10,000, with 2000 on the cell body and 8000 on the dendrites. Indeed, there are so many knobs that the neuron appears to be encrusted with them. The portion of the soma membrane covered by any single synaptic knob is small, but the synaptic knobs are so numerous that, in aggregate, the area covered by them all is often 40 % of the total membrane area. In the cerebral cortex, it has been calculated that 98 % of the synapses are on dendrites and only 2 % are on cell bodies.)

b) Structure of synapses (All synapses consist of: presynaptic membrane, postsynaptic membrane, synaptic cleft, subsynaptic membrane.)

c) Excitatory postsynaptic porential (Single stimuli applied to the sensory nerves in the experimental situation described above characteristically do not lead to the formation of a propagated action potential in the postsynaptic neuron. Instead, the stimulation produces either a transient, partial depolarization or a transient hyperpolarization.

The depolarizing response produced by a single stimulus to the proper input begins about 0,5 ms after the afferent impulse enters the spinal cord. It reaches its peak 1-1,5 ms later and then declines exponentially, with a time constant (time required for the response to decay to 1/e, or 1/2,718 of its maximum) of about 4 ms. During this potential, the excitability of the neuron to other stimuli is increased, and consequently the potential is called an excitatory postsynaptic potential (EPSP).

The EPSP is due to depolarization of the postsynaptic cell membrane immediately under the active synaptic knob. The area of inward current flow thus created is so small that it will not drain off enough positive charges to depolarize the whole membrane. Instead, an EPSP is inscribed. The EPSP due to activity in one synaptic knob is small, but the depolarizations produced by each of the active knobs summate.

Summation may be spatial or temporal. When activity is present in more than one synaptic knob at the same time, spatial summation occurs and activity in one synaptic knob is said to facilitate activity in another to approach the firing level. Temporal summation occurs if repeated afferent stimuli cause new EPSPs before previous EPSPs have decayed. The EPSP is therefore not an all or none response but is proportionate in size to the strength of the afferent stimulus. If the EPSP is large enough to reach the firing level of the cell, a full-fledged action potential is produced.)

d) Synaptic delay (When an impulse reaches the presynaptic terminals, there is an interval of at least 0,5 ms, the synaptic delay, before a response is obtained in the postsynaptic neuron. The delay following maximal stimulation of the presynaptic neuron corresponds to the latency of the EPSP and is due to the time it takes for the synaptic mediator to be released and to act on the membrane of the postsynaptic cell. Because of it, conduction along a chain of neurons is slower if there are many synapses in the chain than if there are only a few. This fact is important in comparing, for example, transmission in the lemniscal sensory pathways to the cerebral cortex and transmission in the reticular activating system. Since the minimum time for transmission across one synapse is 0,5 ms, it is also possible to determine whether a given reflex pathway is monosynaptic or polysynaptic (contains more than one synapse) by measuring the delay in transmission from the dorsal to the ventral root across the spinal cord.)

Types of Synapses—Chemical and Electrical

There are two major types of synapses: the chemical synapse and the electrical synapse.

Almost all the synapses used for signal transmission in the central nervous system of the human being are chemical synapses. In these, the first neuron secretes a chemical substance called a neurotransmitter (or often called simply transmitter substance) at the synapse, and this transmitter in turn acts on receptor proteins in the membrane of the next neuron to excite the neuron, inhibit it, or modify its sensitivity in some other way. More than 40 transmitter substances have been discovered thus far. Some of the best known are acetylcholine, norepinephrine, histamine, gamma-aminobutyric acid (GABA), glycine, serotonin, and glutamate.

Electrical synapses, in contrast, are characterized by direct open fluid channels that conduct electricity from one cell to the next. Most of these consist of small protein tubular structures called gap junctions that allow free movement of ions from the interior of one cell to the interior of the next. Only a few gap junctions have been found in the central nervous system. However, it is by way of gap junctions and other similar junctions that action potentials are transmitted from one smooth muscle fiber to the next in visceral smooth muscle and from one cardiac muscle cell to the next in cardiac muscle.

"One-Way" Conduction at Chemical Synapses. Chemical synapses have one exceedingly important characteristic that makes them highly desirable as the form of transmission of nervous system signals. They always transmit the signals in one direction—that is, from the neuron that secretes the transmitter substance, called the presynaptic neuron, to the neuron on which the transmitter acts, called the postsynaptic neuron. This is the principle of one-way conduction at chemical synapses, and it is quite different from conduction through electrical synapses, which usually can transmit signals in either direction.

Think for a moment about the extreme importance of the one-way conduction mechanism. It allows signals to be directed toward specific goals. Indeed, it is this specific transmission of signals to discrete and highly focused areas both in the nervous system and at the terminals of the peripheral nerves that allows the nervous system to perform its myriad functions of sensation, motor control, memory, and many others transmission of nervous system signals. They always transmit the signals in one direction—that is, from the neuron that secretes the transmitter substance, called the presynaptic neuron, to the neuron on which the transmitter acts, called the postsynaptic neuron. This is the principle of one-way conduction at chemical synapses, and it is quite different from conduction through electrical synapses, which usually can transmit signals in either direction.

Physiologic Anatomy of the Synapse

А typical anterior motor neuron in the anterior horn of the spinal cord. It is composed of three major parts: the soma, which is the main body of the neuron; a single axon, which extends from the soma into a peripheral nerve that leaves the spinal cord; and the dendrites, which are great numbers of branching projections of the soma that extend as much as 1 millimeter into the surrounding areas of the cord.

As many as 10,000 to maybe more than 200,01 small knobs called presynaptic terminals lie on the is faces of the dendrites and soma of the motor neuron about 80 to 95 per cent of them on the dendrites air only 5 to 20 per cent on the soma. These presynaptic terminals are the ends of nerve fibrils that original from many other neurons. Later, it will become evade that many of these presynaptic terminals are exactors—that is, they secrete a transmitter substance the excites the postsynaptic neuron; many others are inhibitory—they secrete a transmitter substance that inhibit the postsynaptic neuron.

Neurons in other parts of the cord and brain differ markedly from the anterior motor neuron in the sis of the cell body; the length, size, and number (dendrites, ranging in length from almost zero to man centimeters; the length and size of the axon; an the number of presynaptic terminals, which ma range from only a few to as many as 200,000. These differences make neurons in different parts of the nervous system react differently to incoming signals are therefore, perform different functions.

Presynaptic Terminals. Electron microscopic studies о the presynaptic terminals show that they have varies & anatomical forms, but most resemble small round о oval knobs and, therefore, are called terminal knobs, buttons, end-feet, or synaptic knobs.

The basic structure of the pre synaptic terminal. It is separated from the postsynaptic neuronal soma by a synaptic cleft having a width use ally of 200 to 300 angstroms. The terminal has two internal structures important to the excitatory or inhibitory functions of the synapse: the transmitter vesicle: and the mitochondria. The transmitter vesicles contain the transmitter substance that, when released into the synaptic cleft either excites or inhibits the postsynaptic neuron—excites if the neuronal membrane contains excitatory receptors, inhibits if the membrane contains inhibitory receptors. The mitochondria provide adenosine triphosphate, which supplies the energy to synthesize new transmitter substance.

When an action potential spreads over a presynaptic terminal, the depolarization of the membrane causes a small number of vesicles to empty into the cleft. The released transmitter in turn causes an immediate change in the permeability characteristics of the postsynaptic neuronal membrane, and this leads to excitation or inhibition of the postsynaptic neuron, depending on the neuron's receptor characteristics.

The cell membrane covering the presynaptic terminals, which is called the presynaptic membrane, contains large numbers of voltage-gated calcium channels. This is quite different from the other areas of the nerve fiber, which contain much fewer of these channels. When an action potential depolarizes the terminal, the channels open and allow large numbers of calcium ions to flow into the terminal. The quantity of transmitter substance that is then released into the synaptic cleft is directly related to the number of calcium ions that enter the terminal. The precise mechanism by which the calcium ions cause this release is not known, but it is believed to be the following.

When the calcium ions enter the presynaptic terminal, it is believed that they bind with special protein molecules on the inside surface of the presynaptic membrane, called release sites. This binding in turn causes transmitter vesicles in the terminal to fuse with the release sites and to open through the membrane to the exterior by the process called exocytose. A few vesicles usually release their transmitter into the cleft after each single action potential. For those vesicles that store the neuro-transmitter acetylcholine, between 2000 and 10,000 molecules of acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal to transmit from a few hundred to more than 10,000 action potentials.

Action of the Transmitter Substance on the

Postsynaptic Neuron—Function of "Receptor Proteins" At the synapse, the membrane of the postsynaptic neuron contains large numbers of receptor proteins, also shown in Figure 3. The molecules of these receptors have two important components: a binding component that protrudes outward from the membrane into the synaptic cleft—here it binds with the neurotransmitter from the presynaptic terminal—and an ionophore component that passes all the way through the membrane to the interior of the postsynaptic neuron. The ionophore in turn is one of two types: an ion channel that allows passage of specified types of ions through the membrane or a "second messenger" activator that is not an ion channel but instead is a molecule that protrudes into the cell cytoplasm and acti- vates one or more substances inside the postsynaptic neuron. These substances in turn serve as "second messengers" to change specific internal cellular functions.

Ion Channels. The ion channels in the postsynaptic neuronal membrane are usually of two types: (1) cation channels that most often allow sodium ions to pass when opened but sometimes allow potassium and/or calcium ions as well, and (2) anion channels that allow mainly chloride ions to pass but also minute quantities of other anions.

The cation channels that conduct sodium ions are lined with negative charges. These charges attract the positively charged sodium ions into the channel when the channel diameter increases to a size larger than that of the hydrated sodium ion. But those same negative charges repel chloride ions and other anions and prevent their passage.

For the anion channels, when the channel diameters become large enough, chloride ions pass into the channels and on through to the opposite side, whereas sodium, potassium, and calcium cations are blocked, mainly because their hydrated ions are too large to pass.

We will learn later that opening the cation channels allows positively charged sodium ions to enter, which excites the postsynaptic neuron. Therefore, a transmitter substance that opens cation channels is called an excitatory transmitter. Conversely, opening anion channels allows negative electrical charges to enter, which inhibits the neuron. Therefore, transmitter substances that open these channels are called inhibitory transmitters.

When a transmitter substance activates an ion channel, the channel usually opens within a fraction of a millisecond; when the transmitter substance is no longer present, the channel closes equally rapidly. Therefore, the opening and closing of ion channels provide a means for rapid control of postsynaptic neurons.

Characteristics of Some of the More Important Small-Molecule Transmitters. The most important of the small-molecule transmitters are the following.

Acetylcholine is secreted by neurons in many areas of the brain but specifically by the terminals of the large pyramidal cells of the motor cortex, by several different types of neurons in the basal ganglia, by the motor neurons that innervate the skeletal muscles, by the pre-ganglion neurons of the autonomic nervous system, by the postganglionic neurons of the parasympathetic nervous system, and by some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect: however, it is known to have inhibitory effects at some of the peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves.

Norepinephrine is secreted by the terminals of many neurons whose cell bodies are located in the brain stem and hypothalamus. Specifically, norepinephrine-secreting neurons located in the locus ceruleus in the pones send nerve fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as increasing the level of wakefulness. In most of these areas, norepinephrine probably activates excitatory receptors, but in a few areas, it activates inhibitory receptors instead. Norepinephrine is also secreted by most of the postganglionic neurons of the sympathetic nervous system, where it excites some organs but inhibits others.

Dopamine is secreted by neurons that originate in the substantia nigra. The termination of these neurons is mainly in the striatal region of the basal ganglia. The effect of dopamine is usually inhibition.

Glycine is secreted mainly at synapses in the spinal cord. It probably always acts as an inhibitory transmitter.

GABA is secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. It is believed always to cause inhibition.

Glutamate is secreted by the presynaptic terminals in many of the sensory pathways entering the central nervous system, as well as in many areas of the cerebral cortex. It probably always causes excitation.

Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the hypothalamus. Serotonin acts as an inhibitor of pain pathways in the cord, and its inhibitor action in the higher regions of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep.

Nitric oxide occurs especially in areas of the brain that are responsible for long-term behavior and for memory. Therefore, this transmitter system might help to explain behavior and memory functions that thus far have defied understanding. Nitric oxide is different from other small-molecule transmitters in the mechanisms of its formation in the presynaptic terminal and in its action on the postsynaptic neuron. It is not preformed and stored in vesicles in the presynaptic terminal as are other transmitters. Instead, it is synthesized almost instantly as needed, and it then diffuses out of the presynaptic terminals over a period of seconds rather than being released in vesicular packets. Next, it diffuses into postsynaptic neurons nearby. In the postsynaptic neuron, it usually does not greatly alter the membrane potential but instead changes intracellular metabolic functions that modify neuronal excitability for seconds, minutes, or perhaps even longer.

Neuropeptides

The neuropeptides are an entirely different group of transmitters that are synthesized differently and whose actions are usually slow and in other ways quite different from those of the small-molecule transmitters.

The neuropeptides are not synthesized in the cytosol of the presynaptic terminals. Instead, they are synthesized as integral parts of large-protein molecules by ri-bosomes in the neuronal cell body. The protein molecules then enter the spaces inside the endoplasmic reticulum of the cell body and subsequently the Golgi apparatus, where two changes occur: First, the protein is enzymatically split into smaller fragments, some of which are either the neuropeptide itself or a precursor of it. Second, the Golgi apparatus packages the neuropeptide into minute transmitter vesicles that are released into the cytoplasm. Then the transmitter vesicles are transported all the way to the tips of the nerve fibers by axonal streaming of the axon cytoplasm, traveling at the slow rate of only a few centimeters per day. Finally, these vesicles release their transmitter at the neuronal terminals in response to action potentials in the same manner as for small-molecule transmitters. However, the vesicle is autolyzed and is not reused.

Because of this laborious method of forming the neuropeptides, much smaller quantities of them are usually released than of the small-molecule transmitters. This is partly compensated for by the fact that the neuropeptides are generally a thousand or more times as potent as the small-molecule transmitters. Another important characteristic of the neuropeptides is that they usually cause much more prolonged actions. Some of these actions include prolonged closure of calcium pores, prolonged changes in the metabolic machinery of cells, prolonged changes in activation or deactivation of specific genes in the cell nucleus, and/or prolonged alterations in numbers of excitatory or inhibitory receptors. Some of these effects last for days, but others perhaps for months or years. Our knowledge of the functions of the neuropeptides is only beginning to develop.

Electrical Events During Neuronal Excitation

The electrical events in neuronal excitation have been studied especially in the large motor neurons of the anterior horns of the spinal cord. Therefore, the events described in the next few sections pertain essentially to these neurons. Except for quantitative differences, they apply to many other neurons of the nervous system as well.

Resting Membrane Potential of the Neuronal Soma.

Concentration Differences of Ions Across the Neuronal Somal Membrane. Figure 4 also shows the concentration differences across the neuronal somal membrane of the three ions that are most important for neuronal function: sodium ions, potassium ions, and chloride ions.

At the top, the sodium ion concentration is shown to be great in the extracellular fluid (142 mEq/L) but low inside the neuron (14 mEq/L). This sodium concentration gradient is caused by a strong somal membrane sodium pump that continually pumps sodium out of the neuron.

The figure also shows that the potassium ion concentration is high inside the neuronal soma (120 mEq/L) but low in the extracellular fluid (4.5 mEq/L). It shows that there is also a potassium pump that pumps potassium to the interior.

Special Functions of Dendrites in Exciting Neurons

Large Spatial Field of Excitation of the Dendrites.

The dendrites of the anterior motor neurons extend for 500 to 1000 micrometers in all directions from the neuronal soma. Therefore, these dendrites can receive signals from a large spatial area around the motor neuron. This provides vast opportunity for summation of signals from many separate presynaptic nerve fibers.

It is also important that between 80 and 95 per cent of all the presynaptic terminals of the anterior motor neuron terminate on the dendrites, in contrast to only 5 to 20 per cent terminating on the neuronal soma. Therefore, the preponderant share of the excitation is provided by signals transmitted by way of the dendrites.

Most Dendrites Cannot Transmit Action Potentials— But They Can Transmit Signals by Electrotonic Conduction. Most dendrites fail to transmit action potentials because their membranes have relatively few voltage-gated sodium channels, so that their thresholds for excitation are too high for action potentials to occur. Yell they do transmit electrotonic current down the dendrites to the soma. Stimulation (or inhibition) of the neuron by this curer has special characteristics, as follows.

Decrement of Electrotonic Conduction in the Dendrites—Greater Excitatory (or Inhibitory). Effect by Synapses near the Soma. In Figure 5, number excitatory and inhibitory synapses are shown stimulating the dendrites of a neuron. On the two dendrites to the left, there are excitatory effects near the tip ends; not the high levels of excitatory postsynaptic potentials these ends—that is, the less negative membrane potentials at these points. However, a large share of the excitatory postsynaptic potential is lost before it reaches the soma. The reason for this is that the dendrites are long, and their membranes are also thin and excessively permeable to potassium and chloride ions, making them "leaky" to electric current. Therefore, before the excitatory potentials can reach the soma, a large share of the potential is lost by leakage through the membrane. This decrease in membrane potential as it spreads electrotonically along dendrites toward the soma is called decremental conduction.

It is also obvious that the farther the excitatory synapse is from the soma of the neuron, the greater will be the total decrement of conduction. Therefore, those synapses that lie near the soma have far more effect in causing neuron excitation or inhibition than those that lie far away from the soma.

Summation of Excitation and Inhibition in Dendrites.

The uppermost dendrite of Figure 5 is shown to be stimulated by both excitatory and inhibitory synapses. At the tip of the dendrite is a strong excitatory postsynaptic potential, but nearer the soma are two inhibitory synapses acting on the same dendrite. These inhibitory synapses provide a hyperpolarizing voltage that completely nullifies the excitatory effect and indeed transmits a small amount of inhibition by electrotonic conduction toward the soma. Thus, dendrites can sum-mate excitatory and inhibitory postsynaptic potentials in the same way that the soma can.

Also shown in the figure are several inhibitory synapses located directly on the axon hillock and initial axon segment. This location provides especially powerful inhibition because it has the direct effect of increasing the threshold for excitation at the very point where the action potential is normally generated.

"Excitatory State." The "excitatory state" of a neuron is defined as the summated degree of excitatory drive to the neuron. If there is a higher degree of excitation than inhibition of the neuron at any given instant, then it is said that there is an excitatory state. Conversely, if there is more inhibition than excitation, then it is said that there is an inhibitory state.

When the excitatory state of a neuron rises above the threshold for excitation, the neuron will fire repetitively as long as the excitatory state remains at this level.

Some neurons in the central nervous system fire continuously because even the normal excitatory state is above the threshold level. Their frequency of firing can usually be increased still more by further increasing their excitatory state. The frequency can be decreased, or firing can even be stopped, by superimposing an inhibitory state on the neuron.

Thus, different neurons respond differently, have different thresholds for excitation, and have widely differing maximal frequencies of discharge. With a little imagination, one can readily understand the importance of having neurons with these many types of response characteristics to perform the widely varying functions of the nervous system

Summation of Excitation and Inhibition in Dendrites.

If there is a higher degree of excitation than inhibition of the neuron at any given instant, then it is said that there is an excitatory state. Conversely, if there is more inhibition than excitation, then it is said that there is an inhibitory state.

When the excitatory state of a neuron rises above the threshold for excitation, the neuron will fire repetitively as long as the excitatory state remains at this level.