Spread of excitation in chronically lesioned mouse hippocampus determined by laser scanning microscopy

Fast optical recordings by means of laser scanning microscopy in conjunction with a voltage-sensitive dye (RH 414) were performed to monitor the spatio-temporal spread of neuronal activity in CA3/CA4-lesioned C57BL6 mouse hippocampal slices prepared approximately 3 months after intracerebroventricular kainic acid (KA) injection. The aim of our study was to assess the effects of a circumscribed neuronal loss on the propagation of electrical activity along the trisynaptic hippocampal circuit. Both in physiological bathing solution and in bicuculline (10 microM), hilar stimulation failed to activate the downstream pathway, so that, under these conditions, the chronically disinhibited CA1 region appeared to be effectively isolated from burst activity arising upstream; however, epileptiform discharges evoked in zero Mg2+ solution were reliably transmitted from the dentate gyrus to the CA1 region. That these bursts were indeed spreading across the lesion, and not along newly formed connections (e.g., between dentate gyrus and CA1), was confirmed by acute transection experiments of the Schaffer collateral/commissural pathway, which completely abolished translesional burst propagation. The fact that the surviving CA3-CA1 connections are unable to trigger epileptiform bursts after suppression of GABAergic inhibition suggests that the lesioned region might serve as a filter that shields hyperexcitable CA1 neurons from epileptic activity arising upstream, in particular from chronically disinhibited granule cells of the dentate gyrus. An impaired GABAergic inhibition will thus only have minor facilitating effects on seizure propagation in the hippocampus of CA3-lesioned animals.