METABOTROPIC GLUTAMATE-RECEPTOR ACTIVATION MODULATES EPILEPTIFORM ACTIVITY IN THE HIPPOCAMPUS

Synchronous neuronal activity that resembles interictal epileptiform d ischarges occurs in hippocampal slices if there is an imbalance of inh ibitory and excitatory synaptic activity. Antagonists of the GABA(A) r eceptor and agonists of the ionotropic glutamate receptors are convuls ants that produce epileptiform discharges in hippocampal slices. We ev aluated the effects of activation of the metabotropic class of glutama te receptors on epileptiform activity produced by convulsants. The met abotropic glutamate agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarb oxylic acid (ACPD, 30-100 mu M) accelerated the rate of interictal epi leptiform discharges produced by either bicuculline methiodide or 4-am inopyridine and had minimal effects on discharges produced by high [K](o). The increase in rate was associated with a significant decrease in the amplitude and duration of the afterhyperpolarization that follo ws the paroxysmal depolarizing shift, the intracellular correlate of t he interictal epileptiform discharge. A modest increase in input resis tance (similar to 10%) accompanied the rate increase. beta-adrenergic or muscarinic agonists, neurotransmitters that also decrease the after hyperpolarization, acted synergistically with ACPD (100 mu M) to incre ase the control rate of bicuculline-induced interictal discharges by m ore than eight-fold. Antagonists of beta-adrenergic or muscarinic rece ptors reduced, but did not block, the acceleration of bicuculline-indu ced discharge rate produced by 30 mu M ACPD. The results show that met abotropic glutamate receptors enhance the rate of interictal epileptif orm discharges produced by bicuculline or 4-aminopyridine. ACPD had no effect on interictal epileptiform activity induced by high [K+](o), a finding that may indicate that in high [K+](o) conditions the metabot ropic receptor is activated or that the effects of high [K+](o) alread y reduced the effect of depolarizing currents that are enhanced by ACP D. The acceleration in interictal discharge rate was associated with a reduction in the afterhyperpolarization that follows the paroxysmal d epolarizing shift and this action appears to be important in determini ng the synchronization of neurons and the rate of interictal epileptif orm discharges. Furthermore, interaction between mGluR activation and either muscarinic or beta-adrenergic activation may be important for s eizure generation. (C) 1997 IBRO. Published by Elsevier Science Ltd.