Abstracts

Rationale: Status epilepticus (SE) can precede the development of temporal lobe epilepsy (TLE) and cognitive deficits. SE-induced loss of synaptodendritic elements and microgliosis in the hippocampus may play a role in this pathophysiology. We found a spatiotemporal correlation between dendritic loss and microgliosis (Schartz et al. 2016) and hyperactivation of the immune classical complement (C) pathway in the hippocampus (Schartz et al. submitted). This pathway is initiated by C1q and leads to C3 activation, which contributes to the microglial removal of extranumerary synapses in the developing brain and to a pathological elimination of hippocampal synapses in models of neurodegenerative disorders. Therefore, we hypothesized that SE-induced activation of C1q-C3 may promote the loss of hippocampal synaptic proteins and cognitive deficits in a rat model of acquired TLE.  Methods: To determine the role of the classical complement pathway in these SE-induced changes we used the C1-esterase inhibitor (C1-INH) to block complement activation downstream of C1q after an episode of SE. Rats were given pilocarpine to induce SE, which was stopped after 1hr with diazepam.  Controls were given saline. Four, 24 and 48 hrs after SE, C1-INH or Vehicle (V) were administered in the following groups: Control+V, SE+V, and SE+C1-INH. Two weeks after SE, hippocampal-dependent spatial memory and learning were evaluated using the Barnes Maze (BM). Hippocampal synaptic proteins (VGlut, VGat, PSD95) were measured using western blot (WB).  Results: In the BM rats used spatial cues to find a hidden platform on an open circular platform. The escape latency of the Control+V group decreased over 4 training days (p p p p Conclusions: Our findings did not support the hypothesis that C1-INH would protect against SE-induced hippocampal synaptic changes and cognitive deficits. However, they still support that activation of C3 correlates with loss of hippocampal synaptic proteins and memory deficits. Blocking C1q signaling may have provoked compensatory activation of the alternative complement pathway, which also leads to C3 activation. This would suggest a role for C3 in synaptodendritic and cognitive pathologies associated with SE, which our future studies will investigate using C3 null mice. Funding: American Epilepsy Society, Grant #: 411837 (ALB)