Chemical synapses are biological junctions through which neurons signal to each other and to non-neuronal cells such as those inmuscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.
At a chemical synapse, one neuron releases neurotransmitter molecules into a small space (the synaptic cleft) that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis. These molecules then bind to receptors on the postsynaptic cell’s side of the synaptic cleft. Finally, the neurotransmitters must be cleared from the synapse through one of several potential mechanisms including enzymatic degradation or re-uptake by specific transporters either on the presynaptic cell or possibly by neuroglia to terminate the action of the transmitter.
The adult human brain is estimated to contain from 1014 to 5 × 1014 (100–500 trillion) synapses. Every cubic millimeter of cerebral cortex contains roughly a billion (short scale, i.e. 109) of them.
The word “synapse” comes from “synaptein”, which Sir Charles Scott Sherrington and 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 also exist. Without a qualifier, however, “synapse” commonly means chemical synapse.
Synaptic transmission can be changed by previous activity. These changes are called synaptic plasticity and may result in either a decrease in the efficacy of the synapse, called depression, or an increase in efficacy, called potentiation. These changes can either be long-term or short-term. Forms of short-term plasticity include synaptic fatigue or depression and synaptic augmentation. Forms of long-term plasticity include long-term depression and long-term potentiation. Synaptic plasticity can be either homosynaptic (occurring at a single synapse) or heterosynaptic (occurring at multiple synapses).
Neurotransmitters also known as chemical messengers, are endogenous chemicals that enableneurotransmission. They transmit signals across a chemical synapse, such as a neuromuscular junction, from one neuron (nerve cell) to another “target” neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps to convert them. Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers are unknown but more than 100 chemical messengers have been identified.
There are four main criteria for identifying neurotransmitters:
- The chemical must be synthesized in the neuron or otherwise be present in it.
- When the neuron is active, the chemical must be released and produce a response in some target.
- The same response must be obtained when the chemical is experimentally placed on the target.
- A mechanism must exist for removing the chemical from its site of activation after its work is done.
However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term “neurotransmitter” can be applied to chemicals that:
- Carry messages between neurons via influence on the postsynaptic membrane.
- Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
- Communicate by sending reverse-direction messages that have an impact on the release or reuptake of transmitters.
The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify either the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.
- Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid (GABA), glycine
- Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S)
- Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SER, 5-HT)
- Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc.
- Peptides: somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides
- Purines: adenosine triphosphate (ATP), adenosine
- Others: acetylcholine (ACh), anandamide, etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are “co-released” along with a small-molecule transmitter. Nevertheless, in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.
Single ions (such as synaptically released zinc) are also considered neurotransmitters by some, as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.
The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is Gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.
Here are a few examples of important neurotransmitter actions:
- Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are “modifiable”, i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes. Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, Amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington disease, and Parkinson’s disease.
- GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.Correspondingly, glycine is the inhibitory transmitter in the spinal cord.
- Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems. It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system. It is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic receptors.
- Dopamine has a number of important functions in the brain; this includes regulation of motor behavior, pleasures related to motivation and also emotional arousal. It plays a critical role in the reward system; people with Parkinson’s disease have been linked to low levels of dopamine and people with schizophrenia have been linked to high levels of dopamine.
- Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluidand brain tissue.
- Norepinephrine which focuses on the central nervous system, based on patients sleep patterns, focus and alertness. It is synthesized from tyrosine.
- Epinephrine which is also synthesized from tyrosine takes part in controlling the adrenal glands. It plays a role in sleep, with ones ability to stay become alert, and the fight-or-flight response.
- Histamine works with the central nervous system (CNS), specifically the hypothalamus (tuberomammillary nucleus) and CNS mast cells.