Repeated administration of group I mGluR antagonists prevents seizure-induced long-term aberrations in hippocampal synaptic plasticity

Abstract

Kindling induced by repeated application of the convulsant pentylenetetrazole (PTZ) is a validated model of epilepsy and epilepsy-related neuromorphological, neurophysiological and behavioural alterations. In this study, we examined whether kindling-induced long-term aberrations in hippocampal synaptic plasticity can be prevented by application of group I mGluR antagonists. Kindling resulted in a higher magnitude of long-term potentiation (LTP) induced by a strong high-frequency stimulation in the hippocampal CA1 region in vitro. When the specific mGluR1 antagonist LY 367385 (0.40 μMol) or the specific mGluR5 inhibitor MPEP (0.06 μMol) were given 30 min prior to PTZ, this kindling-induced enhancement of LTP was almost completely prevented. In addition, application of MPEP led to an impaired maintenance of population spike LTP in kindled animals. LY 367385 applied to unkindled control animals caused a reduction of the initial magnitude of population spike LTP. MPEP, in contrast, left the initial magnitude untouched but resulted in a faster decay of potentiation. A single administration of LY 367385 (200 μM) and MPEP (50 μM), respectively, directly into the bath had almost no effect. Our data suggest that the long-lasting aberrations of hippocampal synaptic plasticity induced by the repeated occurrence of generalized epileptic seizures ultimately require a concurrent operation of mGluR1 and mGluR5.