Control of neocortical excitability by metabotropic glutamate receptors.

摘要

The endogenous excitatory amino acid glutamate is known to act on several distinct receptors in the central nervous system. Glutamate-sensitive receptors can be classified as ionotropic (coupled to membrane ion channels) or metabotropic (coupled to intracellular second messenger systems via G-proteins). The focus of this thesis was to investigate the control of neocortical excitability by metabotropic glutamate receptors (mGluRs). In the first study, I describe the reversible presynaptic reduction in transmitter release by mGluR activation in the adult rat neocortex. Both excitatory and directly evoked inhibitory synaptic transmission were decreased, and the mGluR pharmacology was investigated. In addition to the suppressive action of presynaptic mGluRs on synaptic transmission, direct activation of postsynaptic mGluRs increases neuronal excitability in the neocortex. The second study investigates the mGluR pharmacology and the second messenger signaling pathways involved in the mGluR-mediated reduction in spike frequency adaptation. The results suggest a membrane-delimited action of G-proteins on Ca{dollar}sp{lcub}2+{rcub}{dollar}-activated K{dollar}sp+{dollar} channels to reduce spike adaptation. When synaptic inhibition is reduced by convulsant agents, e.g., bicuculline, epileptiform discharges can be evoked in adult neocortical brain slices. In the third study, I investigated the effects of mGluR activation on epileptiform activity. The results indicate that mGluR activation has significant suppressive effects on epileptiform activity in the adult rat neocortex maintained in vitro. More excitable than adult tissue, brain slices obtained from immature rat neocortex develop ictal-like paroxysmal activity in the presence of bicuculline. In the fourth study, the investigation of mGluR actions in the disinhibited immature neocortex indicates that, during the early postnatal period, activation of neocortical mGluRs has significant facilitatory as well as suppressive effects on bicuculline-induced epileptiform activity. My results suggest that expression of mGluR subtypes may differ between cortical laminae, neuronal subpopulations, and pre- versus postsynaptic localizations. Additionally, these differences appear to be developmentally regulated. Taken together, these studies indicate a substantial neuromodulatory function for the mGluRs in controlling the excitability of the neocortex: the input-output dynamics of cortical circuitry under normal and pathophysiological conditions could be altered markedly by mGluR activation, particularly if the mGluRs were activated by synaptically released glutamate.