Synapse
A chemical synapse is a specialized junction through which neurons transmit information to each other or to non-neuronal cells such as muscles or glands. They are called chemical synapses because the electrical signal from the neuron to the target cell is transmitted via chemical messengers, called neurotransmitters.
Chemical synapses allow the neurons to communicate and to form interconnected neural circuits. They are thus crucial to the biological computations that underlie perception and thought. They also provide the means through which the nervous system connects to and controls the other systems of the body.
History of synapses
In the second half of the nineteenth century there were two vigorously debated hypothesis about the brain structure. Proponents of the cell theory considered that the brain consisted of independent units, which we now call the neurons; while others thought of as a continuous web-like reticulum, called syncytium. The debate remained until the late nineteenth century, when the electron microscopy eventually revealed the presence of the cells, which have their own plasma membrane and make contacts, which we now call the synapses. Ramon y Cajal with Golgi staining method was able to describe the differences between classes of neurons and precise connections between them. Later, however, electron microscopy and other techniques have showed that some neurons possess channels, called connexons, which permit direct flow of ions and other small molecules through the membrane. This type of connection now is called electrical transmission, and the contacts between the cells are called electrical synapses.
The word "synapse" comes from "synaptein" which Sir Charles Scott Sherrington and his colleagues coined from the Greek "syn-" meaning "together" and "haptein" meaning "to clasp". The "synapse" by itself most commonly refers to a chemical synapse.
The first synapse investigations were done on nerve-muscle synapse by Dale at 1936.[1]
Structure of the chemical synapse
The nerve cell, transmitting the signal, is called the presynaptic cell. Its target, receiving the signal, is called the postsynaptic cell. The presynaptic cell transmits the signal from the swollen tips of its axon’s branches, called presynaptic terminals, also called the synaptic button or bouton. The part of synapses where neurotransmitter is released is called the active zone. The presynaptic terminals usually end on the postsynaptic neuron’s dendrites, soma, or, less often, on the axon. The presynaptic cell does not make an anatomical contact with the postsynaptic cell since two cells are separated by a space, the synaptic cleft, which is about 20- 40 nm wide.[2] 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.
Chemical synapses can vary in the size and shape. Under the electron microscopy synapses are seen either as symmetric or asymmetric. Asymmetric, or excitatory synapses, are responsible for excitatory inputs, while symmetric ones are called inhibitory synapses and transmit inhibitory inputs.
Number of synapses one neuron makes varies greatly. The average neuron makes about 1000 synapses and can receive as many as 10,000 synases. The Purkinje cell of the cerebellum receives up to 100,000 inputs.[3] Early during the development neurons make many synapses, later the number declines, reaching the level of adulthood. The process is called activity dependent synapse elimination, when active synapses are reinforced and inactive ones are eliminated. Number of synapses can change even in the adult animals, making conditions for synaptic plasticity. Adult human brain can have from 1015 to 5 × 1015 synapses.
Signaling across chemical synapses
Direct synaptic transmission
Within the presynaptic nerve terminal, vesicles containing neurotransmitter sit "docked" at the synaptic membrane and ready to release the neurotransmitter. The release of neurotransmitter, the exocytosis, is triggered by the arrival of a nerve impulse (or action potential). The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels. Calcium ions then trigger a biochemical cascade which results in vesicles fusing with the presynaptic membrane and releasing their contents to the synaptic cleft. Vesicle fusion is driven by the action of a set of proteins, known as SNAREs. The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles.
After neurotransmitter is released to the synaptic cleft, it can bind ionotropic or metabotropic postsynaptic receptors. During direct synaptic transmission, neurotransmitters bind ionotropic receptors which are themselves ion channels, and change the receptor conformation. As a result, ion channels open and the ions flow in or out of the cell, changing the membrane potential. The resulting change in voltage is called a postsynaptic potential.
Whether an effect is excitatory or inhibitory depends on what type(s) of ion channel conduct the postsynaptic current, which in turn is a function of the type of receptors and neurotransmitter employed at the synapse. In the case of excitatory synapses, positively charged ions move into the postsynaptic cell, depolarizing the cell and making it more excitable. At inhibitory synapses negatively charged ions pass through the membrane and hyperpolarize the cell. In the mammalian central nervous system the main excitatory neurotransmitter is glutamate, while the glycine and GABA are the major inhibitory neurotransmitters. Other important neurotransmitters in the mammalian CNS, acting on ionotropic receptors, are purines, acetylcholine, serotonin, dopamine and others.
Direct synaptic transmission through ionotropic receptors is fast, taking several milliseconds to transmit the signal.
Indirect synaptic transmission
At indirect synaptic transmission, after neurotransmitter is being released, it binds to the metabotropic postsynaptic receptors, which are usually G-protein coupled receptors. When these receptors are activated, they produce intracellular second messangers, which usually are enzymes. Second messangers then activate ion channels through phosphorilation, letting the ions pass into the membrane. Metabotropic receptors can activate ion channels directly, they can also activate another enzymes, changing the neuron excitability. Usually potassium and calcium channels are targeted by such indirect action.
Such responses may last seconds, minutes and hours. Indirect synaptic transmission provide a mechanism for an enormous signal amplification, since one G-protein coupled receptor can activate many ion channels.
Regulation of synaptic transmission
The last step in the synaptic transmission is the elimination of the neurotransmitter from the synaptic cleft. This removal prevents the desensitization of the post-synaptic receptors and ensures that succeeding action potentials will elicit the same size postsynaptic potential. The neurotransmitter can be removed because of diffusion, degradation or uptake by glial cells or nerve terminals.
The action of glutamate, glycine, GABA, dopamine, norepinephrine and 5-HT is terminated by uptake of transmitters by specific transport proteins, called transporters. Transporters neurotransmitter into nerve terminals can be packed into the vesicles and released again. ACh molecules in the synaptic cleft are degradated by a specific enzyme acetylcholinesterase, ATP is terminated by hydrolysis. Neuropetides are removed from the synaptic cleft by diffusion. Neurotransmitter degradation or removal is a prompt process, whereas diffusion is a slower one.
The necessity of removal of neurotransmitters and desensitization of receptors and ion channels means that the strength of a synapse may in effect diminish as a train of action potentials arriving in rapid succession. The phenomenon is called frequency dependence of synaptic transmission. The nervous system exploits this property for computational purposes, and can tune its synapses through such means as phosphorylation of the proteins involved. The size, number and replenishment rate of vesicles also are subject to regulation, as are many other elements of synaptic transmission.
Synaptic plasticity
The efficacy of chemical transmission is not fixed, but depends on the ongoing activity in the synapse. These changes can be a short-term, lasting from milliseconds to minutes, and long-term, lasting hours or days.[4] Short periods of synaptic activation can lead in facilitation, depression or augmentation of neurotransmitter release. All these processes change the amount of neurotransmitter released, last seconds and have a presynaptic origin. Posttetanic facilitation also has a presynaptic origin, but it usually lasts for tens of minutes. Repetitive stimulation can result in long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength. The mechanisms of LTP and LTD have both presynpatic and postsynaptic origins.
Integration of synaptic inputs
Generally, if an excitatory synapse is strong, an action potential in the presynaptic neuron will trigger another action potential in the postsynaptic 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 typically forms synapses with many others, and likewise each receives synaptic inputs from many others. When many synapses of a neuron receive excitatory inputs at the same time, the neuron may generate an impulse even though the synapses are weak. This process is known as spatial summation. If only one synapse is active, but it receives many impulses in a short period of time, impulses are also summated. This process is called temporal summation. On the other hand, a pre-synaptic neuron releasing an inhibitory neurotransmitter such as GABA can cause inhibitory postsynaptic potential in the postsynaptic neuron, decreasing its excitability and therefore decreasing the neuron's likelihood to fire an action potential. In this way the output of a neuron may depend on the inputs of many others, each of them may have a different degree of influence, depending on the strength of its synapse and the location on the 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.
Comparison with electrical synapses
An electrical synapse forms 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.[2] 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, current spreads instantaneously, whereas chemical synapses have a delay of about 1 ms. Electrical synapses conduct equally to both directions, while at the chemical synapse the impulse is send only from pre- to postsynaptic neuron. Electrical synapses are found throughout the nervous system, yet are less common than chemical synapses. Electrical and chemical transmission can coexist at a single synapse.[4] Such combined synapses were first found avian ciliary ganglion cells.[5]
References
- ↑ Dale, H. H., Feldberg, W. and Vogt, M. (1936). J.Physiol. 86: 353- 380.
- ↑ 2.0 2.1 Hormuzdi SG, Filippov MA, Mitropoulou G, Monyer H, Bruzzone R (2004). "Electrical synapses: a dynamic signaling system that shapes the activity of neuronal networks". Biochim. Biophys. Acta 1662 (1-2): 113–37. DOI:10.1016/j.bbamem.2003.10.023. PMID 15033583. Research Blogging.
- ↑ 3.0 3.1 Jessell, Thomas M.; Kandel, Eric R.; Schwartz, James H. (2000). Principles of neural science. New York: McGraw-Hill. ISBN 0-8385-7701-6.
- ↑ 4.0 4.1 Martin, A. Robert; Nicholls, John G.; Wallace, Bruce; Paul A. Fuchs (2001). From neuron to brain. Sunderland, Mass: Sinauer Associates. ISBN 0-87893-439-1.
- ↑ Martin, A. R, and Pilar, G. (1963). J.Physiol. 168: 443- 463.