Synapses

Synapses

Nerve pathways carry nerve impulses. A synapse is a junction between any two communicating neu-rons. The actual gap between neurons is known as the synaptic­ cleft. Neurons conduct intracellular commu-nication across these gaps (FIGURE 11-10). The nervous system requires impulse transmission through neuron chains that are functionally connected by synapses.

Axodendritic synapses are those between the axon endings of a neuron and the dendrites of other neurons. Axosomatic synapses are those between axon endings of one neuron and cell bodies (soma) of others. Less common types of synapses include:

■■ Axoaxonal synapses: Occurring between axons

■■ Dendrodendritic synapses: Occurring between dendrites

■■ Somatodendritic synapses: Occurring between cell bodies and dendrites

Neurons may have between 1,000 and 10,000 axon terminals, with synapses being stimulated by an equivalent number of other neurons. Outside the CNS, postsynaptic cells may be other neurons or effec-tor cells (gland or muscle cells).

A synapse between a neuron and a muscle cell is known as a neuromuscular junction. Neurons reg-ulate or control the activities of secretory cells at neu-roglandular junctions. Neurons also function in the innervation of many other types of cells, an example of which is fat cells or adipocytes.

A neuron carrying an impulse into a synapse is called a presynaptic neuron. The neuron receiving this impulse is called a postsynaptic neuron. The process of the impulse crossing the synaptic cleft is called synaptic transmission. Most neurons function as both presynaptic and postsynaptic neurons. Syn-aptic transmission occurs in one direction, carried by biochemicals (neurotransmitters).

Chemical Synapses

Chemical synapses allow the release and reception of chemical neurotransmitters. Most chemical syn-apses are made up of two parts: an axon terminal and a neurotransmitter receptor region. The axon terminal is a knob-like structure of the presynaptic neuron that contains many synaptic vesicles, which are very small membrane-bounded sacs holding thousands of neu-rotransmitter molecules. The neurotransmitter recep-tor region is located on the cell body or on a dendrite.

The synaptic cleft is a fluid-filled space that sepa-rates presynaptic and postsynaptic membranes. Each of these clefts is approximately one-millionth of 1 inch in width. The electrical current from the presynaptic membrane dissipates in each synaptic cleft. There-fore, chemical synapses prevent nerve impulses from being directly transmitted between neurons. Instead, they are transmitted through chemical events that are based on release, diffusion, and receptor binding of neurotransmitter molecules. Neurons, therefore, have unidirectional communication between them.

Complex synaptic terminals exist at each neuro-muscular junction, which contain parts of the endo-plasmic reticulum, mitochondria, and thousands of neurotransmitter-filled vesicles. Synaptic terminals reabsorb breakdown products of neurotransmitters, which are synthesized neurotransmitters from cell bodies, enzymes, and lysosomes. The movement of these materials is called axoplasmic transport, which may be slow or fast occurring in both directions. If anterograde, they move from the cell body to the synaptic terminal and if moving in reverse, they are described as retrograde.

Information is transferred across chemical syn-apses beginning when an action potential arrives at an axon terminal. The voltage-gated calcium ion chan-nels then open, allowing calcium to enter the axon terminal. This entry results in synaptic vesicles releas-ing neurotransmitter via exocytosis. A single nerve impulse reaching the presynaptic terminal causes up to 300 vesicles to empty into the synaptic cleft. A higher impulse frequency causes more ­synaptic vesicles to fuse and release their contents. This has a greater effect on postsynaptic cells. Neurotransmitter diffuses across the synaptic cleft, binding to certain receptors on the postsynaptic membrane. This binding opens ion channels to create graded potentials, after which the neurotransmitter’s effects are terminated.

The events that occur at a cholinergic synapse, involving the release of ACh, begin with the arrival of an action potential, which depolarizes the synap-tic ­terminal. Extracellular calcium ions enter the syn-aptic terminal. This triggers the exocytosis of ACh, which then binds to receptors and depolarizes the postsynaptic­ membrane. ACh is then removed by ­acetylcholinesterase (AchE). This enzyme breaks down ACh via hydrolysis into acetate and choline. Acetate is then absorbed and metabolized by the post-synaptic cell or by other tissues and cells. Choline is actively absorbed by the synaptic terminal so more ACh can be synthesized. This requires use of acetate that is provided by coenzyme A.

Synaptic Delay

Between the arrival of the action potential at the syn-aptic terminal and its effect on the postsynaptic mem-brane, there is a synaptic delay of between 0.2 msec and 0.5 msec. Most of the synaptic delay reflects the time required for calcium influx and neurotransmit-ter release, not in the neurotransmitter’s diffusion. The synaptic cleft is thin and neurotransmitters dif-fuse across it very quickly. During this time, an action potential is able to travel more than 7 cm (3 inches) along a myelinated axon.

In the CNS, the total synaptic delay may be lon-ger than the propagation time along axons. Therefore, reflexes, which are important for survival, utilize only a few synapses, allowing for rapid, automatic responses to stimuli. The less synapses involved, the shorter the total synaptic delay, meaning the faster the response. In our bodies, the fastest reflexes have only one synapse, and a sensory neuron directly controls a motor neuron.

Electrical Synapses

Electrical synapses are less common than chemical synapses, consisting of gap junctions similar to those between certain other cells of the body. Channel pro-teins called connexons connect cytoplasm from nearby neurons, allowing ions and smaller molecules to move directly between neurons. These electrically coupled neurons allow for rapid transmission across electrical synapses. Communication is unidirectional or bidi-rectional, based on the nature of each synapse. While synaptic clefts of chemical synapses act as barriers between neurons, electrical synapses allow ions to move directly from one neuron to another.

This means that all interconnected neurons have synchronized activities. The adult human brain has electrical synapses in areas responsible for specific ste-reotypical movements, such as those that control jerky movements of the eyes. Electrical synapses also make up the axoaxonal synapses of the hippocampus, which is involved in memory and emotions. In embry-onic nervous tissue, electrical synapses are much more prevalent, allowing exchanging of “cues” that guide neurons to connect correctly with each other, during early neuronal development. Over time, chemical synapses replace electrical synapses in certain areas, becoming the large majority of all synapses in the body.

Synaptic Fatigue

Synaptic fatigue occurs when intensive stimulation causes the resynthesis and transport mechanisms of ACh to be unable to keep pace with demands for this neurotransmitter. Before synaptic fatigue occurs, mol-ecules of ACh are recycled, and synaptic terminals are not totally dependent on ACh that is synthesized in cell bodies, and delivered via axoplasmic transport. After synaptic fatigue, synapses weaken until ACh has been replenished.

Synaptic Activity

Graded potentials that develop in the postsynap-tic membrane in response to a neurotransmitter are known as postsynaptic potentials. An excitatory postsynaptic potential (EPSP) is caused by a neu-rotransmitter arriving at the postsynaptic membrane, due to the opening of the chemically gated membrane channels, leading to depolarization of the plasma membrane. An inhibitory postsynaptic potential (IPSP) is a graded hyperpolarization of the postsyn-aptic membrane. It may result from the opening of chemically gated potassium channels, during which time the neuron is described as inhibited­. This is due to a greater than normal depolarizing stimulus required to bring the membrane potential to threshold.

Individual EPSPs have tiny effects on transmem-brane potential, but when they combine through the process of summation, their effects become inte-grated. There are two types of summation: ­temporal summation and spatial summation. Temporal summation­ occurs when stimuli are added in rapid succession at just one synapse that is repeatedly active. Although a typical EPSP lasts only 20 msec, with max-imum stimulation, an action potential can reach the synaptic terminal every millisecond. When a second EPSP arrives before the effects of the first EPSP have disappeared, the effects combine. The degree of depo-larization continually increases.

Spatial summation involves simultaneous stimuli that are applied at different locations, cumulatively affecting the transmembrane potential. Multiple syn-apses are active simultaneously. Each synapse moves sodium ions across the postsynaptic membrane, to produce a graded potential that has localized effects. Cumulative effects occur on the initial segment.

Neurotransmitters

There are about 50 types of neurotransmitters, which are classified chemically and functionally. Neurons may release one or more types. The actions of neurotransmit-ters include effects on sleeping, anger, thinking, hunger, movement, memory, and many other functions. Syn-aptic transmission is commonly affected by either the enhancing or inhibiting effects of neurotransmitters, their destruction, or the blocking of receptor binding. Anything that reduces neurotransmitter activity may slow the brain’s ability to communicate with the rest of the body. Usually, neurotransmitters are released at var-ious stimulation frequencies. This helps to create more ordered synaptic transmission. Simultaneous release of two neurotransmitters from the same vesicle does still occur. Therefore, a cell can have multiple effects on its target. A summary of neurotransmitters and their actions is shown in TABLE 11-2.

The membrane of a synaptic knob has increased permeability to calcium ions when an action potential­ reaches it. Calcium ions diffuse inward, and in some synaptic vesicles respond by releasing their contents into the synaptic cleft. Eventually, these vesicles sepa-rate from the membrane and reenter the cytoplasm to pick up more ­neurotransmitters. Neurotransmitters (such as ACh) are decomposed by specific enzymes (such as AchE) . Others are transported back into the synaptic knobs that released them in a process known as reuptake. They may also be transported­ to neurons or neuroglial­ cells that are close to them. These actions prevent neurotransmitters from continually stimulating postsynaptic ­neurons (TABLE 11-3).

Neurotransmitter Chemical Classifications

ACh was the first identified neurotransmitter and is released at neuromuscular junctions. The neuromus-cular junctions that release ACh are also known as cholinergic­ synapses. ACh is synthesized from acetic acid as acetyl coenzyme A and choline via the enzyme cho-line aceyltransferase. It is then transported to synaptic vesicles to be released at a later time. It is then degraded to acetic acid and choline, via the enzyme AchE. Biogenic­ amines include the catecholamines­ and indolamines. The catecholamines include dopamine, epinephrine, and norepinephrine­. The ­indolamines include histamine and serotonin.

Amino acids that have identified roles as neu-rotransmitters include aspartate, glutamate, GABA, and glycine. Peptides or neuropeptides are basically amino acid chains, and include a mediator of pain signals called substance P and substances­ that reduce pain perception while under stress. These substances­ include the endorphins and enkephalins. Examples of endorphins include beta endorphin and ­dynorphin. Neuropeptides called gut–brain peptides are found throughout the gas-trointestinal tract, produced by non-­neural body tissues. These peptides include CCK and somatostatin­.

Purines are chemicals that contain ­nitrogen, which are actually breakdown products of nucleic acids, for example, adenine and guanine. They also include ATP and a part of ATP known as adenosine­. Gases and lipids with neurotransmitter actions include gas-otransmitters and endocannabinoids. Examples of ­gasotransmitters include nitric oxide (NO), carbon monoxide, and hydrogen sulfide. The endocannabi noids are natural neurotransmitters that act at the same receptors as tetrahydrocannabinol, an active ingredient in marijuana. They are lipid soluble and released as needed instead of being stored in ­vesicles.

Neurotransmitter Functional Classifications

Functional classifications of neurotransmitters are based on their excitatory or inhibitory actions. Excit-atory neurotransmitters cause depolarization, whereas inhibitory neurotransmitters cause hyperpolarization. They are also classified based on direct versus indirect actions. Those that act directly bind to and open ion channels. Those that act indirectly cause wider, longer lasting effects via acting through intracellular second messengers (usually G protein pathways). A chemical messenger released by a neuron that affects the strength of synaptic transmission is called a neuromodulator­. Most neuromodulators are neuropeptides, which are small peptide chains that are synthesized and released by synaptic terminals. They usually act by ­binding to receptors in the presynaptic or postsynaptic membranes,­ activating cytoplasmic enzymes. Opioids are neuromodulators that bind to the same group of postsynaptic receptors as the drugs opium and mor-phine. The four classes of CNS opioids are endorphins, enkephalins, endomorphins, and dynorphins.

Overall, neuromodulators have long-term effects that usually appear slowly and trigger responses that have many steps and various involved compounds. They affect the presynaptic membrane and the postsyn-aptic membrane or both. Neuromodulators also may be released alone or with a neurotransmitter. Many neu-rotransmitters and neuromodulators bind to receptors in the plasma membrane, but require a G protein to link between first and second messengers. As a result, an enzyme called adenylate cyclase may be activated. It converts ATP to cyclic adenosine monophosphate (cAMP) at the inner surface of the plasma membrane. cAMP is a second messenger that can open membrane channels and activate intracellular enzymes or both.

Neuronal Pools

Throughout the CNS, the interneurons are organized into a smaller amount of neuronal pools, which are functional groups of interconnected neurons. These pools may have excitatory or inhibitory effects on other pools or peripheral effectors. Neuronal pools may be scattered to involve only neurons in several brain regions or may be localized to just one certain region of the brain or spinal cord. Output of neuronal pools may stimulate or depress activities in the CNS. There are five general patterns of interaction:

■■ Divergence: The spread of information from a neuron to several other neurons or from one neuronal pool to additional neuronal pools. It allows broad distribution of specific input.

■■ Convergence: On a single postsynaptic neuron, several neurons synapse. This means the postsynaptic neuron can be affected by several patterns of activity in the presynaptic neurons. Some motor neurons can be under both conscious and subconscious control as a result of convergence.

■■ Serial processing: Information is relayed from one neuron to another or from one neuronal pool to another. For example, the relay of sensory information from one part of the brain to another.

■■ Parallel processing: When several neurons or neuronal pools process the same information at the same time. This means that divergence must occur first. Parallel processing allows many responses to occur simultaneously.

■■ Reverberation: This resembles a positive feedback loop, because collateral axon branches along the circuit extend back to the source of an impulse and stimulate presynaptic neurons again. A reverberating circuit functions until it is broken by inhibitory stimuli or synaptic fatigue and can occur in one or more neuronal pools.