Prolonged NMDA-Mediated Responses, Altered Ifenprodil Sensitivity, and Epileptiform-Like Events in the Malformed Hippocampus of Methylazoxymethanol Exposed Rats

Abstract

Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. Using whole cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation i.e., rats exposed to methylazoxymethanol (MAM) in utero. Analysis revealed that the late N-methyl-D-aspartate (NMDA) receptor-mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burst-like responses. Focal application of glutamate (10 mM) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 microM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor (NMDAR)-mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDAR function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.