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Fig. 5. Dual-component excitatory postsynaptic potential. Shown are simulated EPSPs based on recordings from hippocampal interneurons in the presence of bicuculline to block postsynaptic GABAergic inhibitory postsy-naptes potential (IPSPs). The AMPA and NMDA receptor components and their algebraic sum are indicated.

In neurons, the kinetics, pharmacologic sensitivity, and Ca2+ permeability of glutamatergic excitatory post synaptic potentials (EPSPs) are strongly influenced by which ionotropic receptors are activated and their subunit composition. Rapid desensitization of AMPA receptors coupled with a slow onset of NMDA receptor activation causes glutamatergic EPSPs in most brain regions to be biphasic (Fig. 5). The early component (lasting 10-20 ms) is dominated by AMPA receptors and the later component (up to several hundred milliseconds) by NMDA receptors.

Three classic features of NMDA receptor activation—glycine action, Mg2+ block, and high Ca2+ permeability—will be summarized briefly. The amino acid glycine was originally reported to potentiate NMDA receptor activation (90), but shortly thereafter was recognized to be an essential coagonist at NMDA receptors (91). NMDA receptors are thus the first and still the only neurotransmitter receptor known to require simultaneous activation by two agonists. Mg2+ is a voltage-dependent channel blocker of NMDA receptors, the block being very strong at hyperpolarized potentials (-80 mV and below), but progressively relieved by depolarization. Synaptic plasticity mediated by NMDA receptors is thus associative in nature, dependent on relief of the Mg2+ block by AMPA receptor-mediated depolarization. NMDA receptor-linked synaptic plasticity is mediated by a high Ca2+ flux through open NMDA receptor channels.

The Ca2+ permeability of AMPA and kainate receptors depends on the presence or absence of editing in the Q/R site, receptors containing exclusively unedited subunits exhibiting much higher Ca2+ permeability than edited receptors (Figs. 3 and 4A,B). Among the AMPA receptors, only the GluR2 subunit mRNA is edited at the Q/R site, with the consequence that receptors lacking GluR2 are about four times more permeable to Ca2+ than to Na+ or K+ (92). A glutamine (Q) or arginine (R) residing in the Q/R site of all known functional kainate receptor subunits also influences their Ca2+ permeability. The homologous amino acid in NMDA receptor subunits is asparagine, which endows all NMDA receptors with high Ca2+ permeability. Indeed, replacement by site-directed mutagenesis of this asparagine with an arginine produces NMDA receptors with very low Ca2+ permeability, similar to that of GluR2-containing AMPA receptors (93). Likewise, replacement of the arginine in GluR2 with glutamine results in a receptor with high Ca2+ permeability. From these findings and others in which the permeability of receptors containing mutations in the pore region has been evaluated (e.g., ref. 94) it is concluded that the cation "selectivity filter" is similar among all glutamate receptors.

The high Ca2+ permeability of NMDA and certain AMPA and kainate receptor channels leads to the transient activation of several Ca2+-activated enzymes, including Ca2+/calmodulin-dependent protein kinase II, the phosphatase calcineurin, protein kinase C, phospholipase A2, phospholipase C, and nitric oxide synthase. Activation of one or more of these enzymes is thought to be at the root of synaptic plasticities mediated by Ca2+ permeable NMDA and AMPA receptors; for example, CAMKII can induce LTP by phosporylating GluRl, leading to potentiation of AMPA receptor-mediated currents (section 3.5.).

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