Abstracts

Rationale: Cognitive impairment impacts the quality of life for 44% of epilepsy patients; however, contributing pathological mechanisms are not understood. The Kcna1-null (KO) mouse is a preclinical model of TLE with associated cognitive impairment. We have previously found that seizures propagate to the lateral hypothalamus (LH) in KO mice, and disease progression is associated with an increase in the number of orexin neurons. LH orexin neurons project to the hippocampus and have a bidirectional modification of synaptic plasticity with high concentrations inhibiting long-term potentiation (LTP) and performance in learning and memory behavioral tasks.  Here, we tested the hypothesis that the KO hippocampus experiences excessive orexin influence that results in impaired synaptic and network correlates of learning and memory.

Methods: Presynaptic plasticity was assessed with paired pulse ratios and postsynaptic plasticity with LTP at the Schaffer-Collateral (SC-CA1) pathway. Spontaneous sharp wave and ripple oscillations in CA1 (implicated in learning and memory consolidation) were also assessed. Hippocampal slices (400 µm) from wild-type (WT) C3HeB/FeJ mice and KO mice were placed over a planar multi-electrode array and perfused with artificial cerebrospinal fluid (aCSF). CA1 stratum radiatum field EPSPs (fEPSPs) were evoked by a paired-pulse (50ms) stimulation of Schaffer Collaterals. Baseline responses were recorded followed by stimulations during perfusion of TCS-1102 (100 nM), a dual orexin receptor antagonist that blocks both orexin receptor 1 and 2. LTP was induced with a theta-burst stimulation protocol. The fEPSP slopes (10%-90%) were used to quantify responses. Spontaneous network oscillations were recorded with and without TCS-1102 (100nM). Sharp waves and ripples in the CA1 region were analyzed. Data were evaluated using two-way ANOVA with p< 0.05 considered significant.