Current Research
A role for the complement system in seizure-induced neuronal and dendritic injury
Funded: R56/RO1NS096234 (R56: 04/01/2018-03/31/2019; RO1: 04/01/2019-03/31/2023).
We are investigating the hypothesis that SE-induced activation of the immune complement system contributes to hippocampal synaptodendritic modifications that promote neuronal hyperexcitability, seizures, and memory deficits. To identify how C3, the central protein of the complement cascade, influences epilepsy in experimental models of SE and acquired temporal lobe epilepsy (TLE) we developed the following aims: 1) To characterize complement activation and associated responses after SE; 2) To determine the contribution of SE-induced C3 activation to neuronal and synaptodendritic changes in the hippocampus; 3) To determine the contribution of SE-induced C3 activation to seizures and hippocampal-dependent memory deficits. To accomplish these, we are using a combination of pharmacogenetic techniques along with biochemical, histological, high/super resolution microscopy, electrophysiology, and behavioral tests.
Trem2 dysfunction in epilepsy
Signaling through the microglial phagocytosis receptor Trem2 is associated with the downstream regulation of microglial survival and proliferation, as well as their phagocytic and inflammatory responses. We found significant decreases in Trem2 that paralleled microgliosis in human drug resistant epilepsy (Wyatt et. al., 2017) and are currently investigating how Trem2 dysfunction contributes to the neuropathology and pathophysiology of epilepsy.
Neuropathological implications of microgliosis during epileptogenesis
We found that during SE-induced epileptogenesis hippocampal microgliosis mirrored the spatiotemporal profile of dendritic loss in a rat model of acquired TLE (Schartz et al., 2016; 2018). Importantly, treatment with rapamycin, an inhibitor of the mTOR pathway and also potent immunosuppressant, during epileptogenesis attenuated microgliosis, dendritic loss, and memory deficits. These observations suggest that microglial proliferation contributes to the dendritic and cognitive decline that follows SE (Brewster et al., 2013). However, because mTOR signaling is fundamental for neuronal and glial homeostasis it is also possible that neuronal mTOR activation plays a role in these events. Therefore, to further elucidate the role of microglial proliferation in the SE-induced hippocampal pathology we are targeting signaling cascades that specifically modulate those functions in microglia, such as the CSF1R signaling pathway (Wyatt-Johnson et al., 2021).
