Status epilepticus (SE) is a neurological emergency characterized by very prolonged, sometimes refractory seizures, and is associated with a 23% mortality. SE is a progressive condition where seizures reduce GABA-mediated inhibition in the hippocampus, which in turn leads to enhanced excitatory neurotransmission and more seizures. We propose to further investigate the mechanisms refractory SE, by testing the hypothesis that enhanced excitatory neurotransmission and altered expression GABAA receptors at synapses maintain refractory SE. In the previous funding period, NMDA receptor antagonists were demonstrated to terminate SE refractory to GABAergic agents. The effect of SE on excitatory neurotransmission was examined in an in vitro model, by exposing hippocampal cultures to low magnesium, and recording excitatory post synaptic currents (EPSCs). There was increased frequency of EPSCS (glutamate release from presynaptic terminals) and activation of NMDA receptors during low-magnesium induced SE. These studies suggested a novel mechanism of increased excitability during SE. We wish to extend these studies to in vivo models of SE and link them to a novel treatment of SE, with the neuropeptide galanin. Experiments outlined in specific aim 1 characterize the effects of SE and anticonvulsant galanin on pre and post synaptic mechanisms in the glutamatergic synapses between Schaffer collaterals and CA1 pyramidal neurons in the hippocampus. In other studies, miniature inhibitory postsynaptic currents (mlPSCs) recorded from granule cells in hippocampal slices prepared from SE-treated animals were smaller in amplitude and slower in decay than those recorded from controls. These mlPSCs recorded from granule cells of SE-treated animals were not enhanced by 30 nM diazepam but those from control animals were robustly enhanced. These studies suggested that the complement of GABAA receptors present at the synapse had changed as a consequence of SE. Experiments proposed in specific aim 2 seek to further characterize the effect of SE on the properties of inhibitory postsynaptic currents (IPSCs) recorded from dentate granule cells by means of patch clamp recordings. The mechanisms of diminished inhibition will be explored further by biochemical and neuroanatomical studies. Preliminary studies suggest that neuronal modulates the rate of endocytosis of GABAA receptors and extrasynaptic receptors may be recruited into synapses during SE. Experiments outlined in specific aim 3 To characterize the effect of SE on GABAA receptor trafficking. ? ?
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