Overview of Synaptic Neurotransmission: Glutamatergic Excitation
Glutamate receptors (GluRs), the major excitatory receptor in the brain, are characterized as ionotropic or metabotropic. Ionotropic GluRs are tetrameric ligand-gated cation channels that induce depolarization of the postsynaptic membrane following the presynaptic release of glutamate. Their actions underlie the cellular models of learning and memory, modulate the excitability of neuronal networks, and are required for synaptic maturation. Ionotropic GluRs can be pharmacologically classified according to their sensitivity to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), Kainate, and N-Methyl-D-aspartic acid (NMDA). AMPA receptors (GluR1-4) evoke excitatory postsynaptic potentials and mediate fast (< 10 ms) synaptic transmission. In contrast, Kainate receptors (GluR5-6 and KA1-2) and NMDA receptors (NR1-3) mediate slower synaptic transmission (10-100 ms) and exert effects on plasticity.
In addition, glutamate can modulate neuronal excitability and synaptic transmission through second messenger signaling pathways. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that function as constitutive dimers. There are eight mGluR subtypes that are differentially expressed in specific neuronal populations throughout the central nervous system. Metabotropic glutamate receptors are classified into three groups based on sequence homology, G protein-coupling, and ligand selectivity. Group I mGluRs (mGluR1 and 5) are predominantly expressed on postsynaptic membranes and function to increase neuronal excitability. In contrast, group II mGluRs (mGluR2 and 3) are expressed on both sides of the synaptic cleft. Group II mGluRs are generally considered as inhibitory and their dysfunction is thought to be central to the development of schizophrenia. Group III (mGluR4, 6, 7, and 8) mGluRs are normally expressed on presynaptic terminals or preterminal axons where they function to inhibit neurotransmitter release.