Chemical synapse

This article is about chemical synapses of the nervous system. For other uses see Synapse (disambiguation).

Chemical synapses are specialized junctions through which the cells of the nervous system signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow the neurons of the central nervous system to form interconnected neural circuits. They are thus crucial to the biological computations that underlie perception and thought. They provide the means through which the nervous system connects to and controls the other systems of the body. A chemical synapse between a motor neuron and a muscle cell is called a neuromuscular junction; this type of synapse is well-understood.

The human brain contains a huge number of chemical synapses; young children have about 10¹⁶ synapses (10 quadrillion). This number declines with age, stabilizing by adulthood. Estimates for adults vary from 10¹⁵ to 5 × 10¹⁵ (1-5 quadrillion) synapses.

The word "synapse" comes from "synaptein", which Sir Charles Scott Sherrington and his colleagues coined from the Greek "syn-" ("together") and "haptein" ("to clasp"). Chemical synapses are not the only type of biological synapse: electrical and immunological synapses exist as well. Without a qualifier, however, "synapse" commonly refers to a chemical synapse.

The signal across a synapse may be regarded as neurocrine, analogous to the types of signaling of the endocrine system (endocrine, paracrine and autocrine).

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Anatomy

  At an archetypal chemical synapse, such as those found at dendritic spines, a mushroom-shaped bud projects from each of two cells toward each other. At this interface, the membranes of the two cells flank each other across a slender gap, the narrowness of which enables signaling molecules known as neurotransmitters to pass rapidly from one cell to the other by diffusion. This gap, which is about 20 nm wide, is known as the synaptic cleft.

Synapses are asymmetric both in structure and in how they operate. Only the so-called presynaptic neuron secretes the neurotransmitter, which binds to receptors facing into the synapse from the postsynaptic cell. The pre-synaptic nerve terminal (also called the synaptic button, bouton, or knob) generally buds from the tip of an axon, while the post-synaptic target surface typically appears on a dendrite, a cell body, or another part of a cell. The parts of synapses where neurotransmitters are released are called the active zones. At active zones the membranes of the two adjacent cells are held in close contact by cell adhesion proteins. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called the postsynaptic density. Proteins in the postsynaptic density serve a myriad of roles, from anchoring and trafficking neurotransmitter receptors into the plasma membrane, to anchoring various proteins which modulate the activity of the receptors. The postsynaptic cell need not be a neuron, and can also be a gland or muscle cell.

Signaling across chemical synapses

Neurotransmitter release

The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action potential) and occurs through an unusually rapid process of cellular secretion, also known as exocytosis: Within the pre-synaptic nerve terminal, vesicles containing neurotransmitter sit "docked" and ready at the synaptic membrane. The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current) (Llinas et al 1981). Calcium ions then trigger a biochemical cascade which results in vesicles fusing with the presynaptic-membrane and releasing their contents to the synaptic cleft with in 180µsec of calcium entry (Llinas et al 1981). Vesicle fusion is driven by the action of a set of proteins in the presynaptic terminal known as SNAREs.

The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles.

Receptor binding

Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules and respond by opening nearby ion channels in the post-synaptic cell membrane, causing ions to rush in or out and changing the local transmembrane potential of the cell. The resulting change in voltage is called a postsynaptic potential. In general, the result is excitatory, in the case of depolarizing currents, or inhibitory in the case of hyperpolarizing currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the post-synaptic current display(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse.

Termination

The signal is terminated by either breakdown of neurotransmitters, or reuptake, the latter is mainly in the presynaptic neuron to avail recycling of the transmitter.

Reuptake

Following fusion of the synaptic vesicles and release of transmitter molecules into the synaptic cleft, small neurotransmitters, such as glycine, are rapidly cleared from the space for recycling by specialized membrane proteins in the pre-synaptic or post-synaptic membrane.

Breakdown

Some neurotransmitters, e.g. acetylcholine and large ones such as peptides, are broken down without any direct reuptake. The choline part of acetylcholine, however, is to a large degree taken up by the presynaptic neuron for recycling. Peptides, on the other hand, must be resynthesized from the neuron soma.

Modulation of synaptic transmission

Synaptic transmission can be modulated by e.g. desensitization, homotropic and heterotropic modulation:

Desensitization

Main article: Desensitization

Desensitization of the post-synaptic receptors is a decrease in response to the same neurotransmitter stimulus. It means that the strength of a synapse may in effect diminish as a train of action potentials arrive in rapid succession--a phenomenon that gives rise to the so-called frequency dependence of synapses. The nervous system exploits this property for computational purposes, and can tune its synapses through such means as phosphorylation of the proteins involved.

Homotropic modulation

Homotropic modulation is a modulation of the presynaptic neuron by its own neurotransmitters, i.e. a form of autocrine signaling. The modulation can include size, number and replenishment rate of vesicles. It is often inhibitory, with the effect of presynaptic inhibition, making the neurotransmitter self-regulating.

One example are neurons of the sympathetic nervous system (SNS), which release noradrenaline, which, besides from affecting postsynaptic receptors, also affect α2-adrenergic receptors, inhibiting further release of noradrenaline. ^[1] This effect is utilized with clonidine to perform inhibitory effects on the SNS.

Heterotropic modulation

Heterotropic modulation is a modulation of presynaptic terminals of nearby neurons. Again, the modulation can include size, number and replenishment rate of vesicles.

One example are again neurons of the sympathetic nervous system, which release noradrenaline, which, in addition, generate inhibitory effect on presynaptic terminals of neurons of the parasympathetic nervous system. ^[1]

Pharmacological intervention

For example, a class of drugs known as selective serotonin reuptake inhibitors or SSRIs affect certain synapses by inhibiting the reuptake of the neurotransmitter serotonin. In contrast, one important excitatory neurotransmitter, acetylcholine, is first broken down into acetate and choline by the enzyme acetylcholinesterase prior to removal from the synapse.

Integration of synaptic inputs

In general, if an excitatory synapse is strong, an action potential in the pre-synaptic neuron will trigger another in the post-synaptic cell, whereas, at a weak synapse, the excitatory post-synaptic potential ("EPSP") will not reach the threshold for action potential initiation. In the brain, however, each neuron forms synapses with many others, and, likewise, each receives synaptic inputs from many others. When action potentials fire simultaneously in several neurons that weakly synapse on a single cell, they may initiate an impulse in that cell even though the synapses are weak. This process is known as summation.^[2] On the other hand, a pre-synaptic neuron releasing an inhibitory neurotransmitter such as GABA can cause inhibitory postsynaptic potential in the post-synaptic neuron, decreasing its excitability and therefore decreasing the neuron's likelihood of firing an action potential. In this way, the output of a neuron may depend on the input of many others, each of which may have a different degree of influence, depending on the strength of its synapse with that neuron. John Carew Eccles performed some of the important early experiments on synaptic integration, for which he received the Nobel Prize for Physiology or Medicine in 1963. Complex input/output relationships form the basis of transistor-based computations in computers, and are thought to figure similarly in neural circuits.

Synaptic strength

The strength of a synapse is defined by the change in transmembrane potential resulting from activation of the postsynaptic neurotransmitter receptors. This change in voltage is known as a postsynaptic potential, and is a direct result of ionic currents flowing through the postsynaptic ion channels. Changes in synaptic strength can be short–term and without permanent structural changes in the neurons themselves, lasting seconds to minutes — or long-term (long-term potentiation, or LTP), in which repeated or continuous synaptic activation can result in second messenger molecules initiating protein synthesis, resulting in alteration of the structure of the synapse itself. Learning and memory are believed to result from long-term changes in synaptic strength, via a mechanism known as synaptic plasticity.

Relationship to electrical synapses

An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic cells known as a gap junction. At gap junctions, cells approach within about 3.5 nm of each other,^[3] a much shorter distance than the 20 to 40 nm distance that separates cells at chemical synapses.^[4] As opposed to chemical synapses, the postsynaptic potential in electrical synapses is not caused by the opening of ion channels by chemical transmitters, but by direct electrical coupling between both neurons. Electrical synapses are therefore faster and more reliable than chemical synapses. Electrical synapses are found throughout the nervous system, yet are less common than chemical synapses.

See also

• Postsynaptic potential

• Excitatory postsynaptic potential
• Inhibitory postsynaptic potential

• Immunological synapse
• Neuromuscular junction
• Neurotransmitter
• Receptor
• Exocytosis

Notes

References

• Llinas R. Sugimori M. and Simon S.M. (1982) PNAS 79:2415-2419
• Llinas R. Steinberg I.Z. and Walton K.D. (1981) Biophys. J. 33: 323-352
• Bear, Mark; Mark F. Bear, Barry W. Connors, Michael A. Paradiso (2001). Neuroscience: Exploring the Brain. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-3944-6. 
• Hormuzdi, SG; Filippov MA, Mitropoulou G, Monyer H, Bruzzone R. (Mar 2004). "Electrical synapses: a dynamic signaling system that shapes the activity of neuronal networks". Biochim Biophys Acta 1662 (1-2): 113-137. doi:10.1016/j.bbamem.2003.10.023. ISSN 0005-2736. PMID 15033583.
• Kandel, Eric R.; James H. Schwartz, Thomas M. Jessell (2000). Principles of Neural Science, 4th edition, New York: McGraw-Hill. ISBN 0-8385-7701-6. 
• Karp, Gerald (2005). Cell and Molecular Biology: concepts and experiments, 4th edition, Hoboken, NJ: John Wiley & Sons, Inc.. ISBN 0-471-46580-1. .
• Nicholls, J.G.; Martin A.R., Wallace B.G., Fuchs P.A. (2001). From Neuron to Brain, 4th edition, Sunderland, MA: Sinauer Associates. ISBN 0878934391.