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The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is γ-aminobutyric acid (GABA).
Glutamate receptors comprise two large families, ligand-gated ion channels called ionotropic receptors and G protein–coupled receptors called metabotropic receptors.
Ionotropic glutamate receptors are divided into three classes—α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, kainate receptors, and N-methyl-D-aspartate (NMDA) receptors—which are named after synthetic ligands that activate them. Individual excitatory synapses typically express several different subtypes of ionotropic glutamate receptors as well as metabotropic receptors.
In contrast to AMPA receptors and kainate receptors, the NMDA receptor has two important biophysical properties. Because it is highly permeable to calcium and is voltage dependent, it allows calcium entry only if the cell is depolarized.
AMPA receptors mediate the vast majority of excitatory synaptic transmission in the brain, whereas NMDA receptors play an important role in triggering synaptic plasticity and, when overactivated, in triggering excitotoxicity.
There are eight subtypes of metabotropic glutamate receptors. When localized to the presynaptic terminal, they inhibit neurotransmitter release. When localized to the postsynaptic membrane, they exert complex modulatory effects through specific signal transduction cascades, which can lead to excitatory or inhibitory effects.
The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration. Several other types of LTP are widespread in the nervous system and are mediated via distinct mechanisms.
Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain.
The GABAA receptor, a ligand-gated chloride channel, and the GABAB receptor, a G protein–coupled receptor, are the two major classes of GABA receptors.
GABAA receptors, which are highly heterogeneous, mediate the bulk of inhibitory synaptic transmission in the brain. Many drugs, most notably benzodiazepines and barbiturates, bind to GABAA receptors and enhance their function.
GABAB receptors are localized both presynaptically, where they inhibit neurotransmitter release, and postsynaptically, where they mediate a slow, inhibitory synaptic response.
Glycine, like GABA, is an inhibitory neurotransmitter that activates receptors that are ligand-gated chloride channels. It is critical in inhibitory neurotransmission in the spinal cord and brainstem.
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Amino acids are the building blocks of proteins involved in normal intermediary metabolism, but they can also function as neurotransmitters. The amino acids glutamate and, to a much lesser extent, aspartate mediate most of the fast excitatory synaptic transmission in the brain; likewise, the amino acids γ-aminobutyric acid (GABA) and, to a lesser extent, glycine mediate most fast inhibitory synaptic transmission. Excitatory amino acids are utilized by nearly every information-bearing circuit in the brain and have been implicated in such diverse pathologic processes as epilepsy, ischemic brain damage, and several psychiatric disorders. In addition, they are necessary for the development of normal synaptic connections. Consequently, amino acid neurotransmitters have been the subject of ...