Little is understood about the mechanisms developmental epilepsy, i.e., the progression from episodic seizures in early-life to chronic epilepsy in adulthood. This progression likely causes childhood learning impairment that could be prevented by a better understanding of the process. A mechanistic connection exists between the expression of an in vitro correlate of learning, long-term depression (LTD), and the consequences of epileptogenesis: LTD induces a near complete removal of a specific GluR subunit (GluR2) from synapses by an N-ethyl-maleimide-sensitive fusion protein (NSF) -dependent mechanism while epileptiform discharges in vitro can produce LTD and epileptogenesis leads to impaired LTD. I hypothesize that these two processes, the expression of LTD and epileptogenesis, saturate the same NSF-GIuR2 interaction that decreases the number of synaptic GIuR2 receptors and results in chronic LTD impairment. First, the developmental progression of LTD in hippocampal slices from control and epileptic rats will be studied using field-recording techniques. Developmental epileptogenesis will be induced with the infra-hippocampal tetanus toxin injection method. It is hypothesized that epileptic rats will develop a progressive impairment in the expression of hippocampal LTD. Second, the developmental interaction of GluRs with NSF will be studied using whole-cell patch-clamp recordings of GluR mediated synaptic currents along with pharmacological agents that modulate the G1uR2-NSF interaction in slice preparations from epileptic and control rats at different ages. It is hypothesized that epileptogenesis will saturate and thus occlude further pharmacological disruption of the GluR2-NSF interaction. Lastly, the impairment of LTD caused by developmental epileptogenesis could alternatively be the result of alterations in the single-channel and/or kinetic properties of GluRs. It is hypothesized that G1uR single- channel conductance and kinetics in epileptic rats, measured by whole- dendrite patch-clamp recordings of GluR mediated synaptic currents and non-stationary noise analysis, will be similar to values measured in control rats.
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