Epilepsy is a seizure disorder that is often comorbid with cognitive disabilities. Prolonged-continuous seizures (status epilepticus; SE) increase the risk for the development of temporal lobe epilepsy (TLE) by remodeling synaptic connectivity in vulnerable neuronal networks such as those of the hippocampus. Extensive evidence supports that SE-induced hippocampal synaptodendritic remodeling orchestrated through glutamate excitotoxicity, apoptosis, and aberrant activation from a number of intracellular signaling cascades is linked to the neuronal hyperexcitability that often results in seizures. Despite these findings, the mechanisms that directly impact neural hyperexcitability remain elusive. A prominent hallmark in the histopathology of SE and epilepsy is activation of microglia, which mediate neuroinflammatory and phagocytic responses. It is well known that microglia-mediated neuroinflammatory mechanisms contribute to seizures; however, a gap remains on the potential role of their phagocytic responses. During and after SE microglia make multiple physical contacts with cortical and hippocampal dendrites, a phenomenon that we recently found in human refractory epilepsy. These contacts may result in the phagocytosis of dendritic structures and thereby modification of neuronal connectivity. Recent studies discovered that C1q and C3 proteins from the immune complement system send ?eat-me? signals that guide microglia to phagocytose extranumerary synapses in the normal developing brain. In addition, C1q and C3 are associated with the pathological removal of hippocampal synaptic structures in models of neurodegenerative disorders. We and others found increases in C1q-C3 mRNA and protein levels in intractable human epilepsy and after SE in experimental models. Therefore, we hypothesized that seizure-induced activation of the immune complement system contributes to hippocampal synaptodendritic modifications that promote neuronal/network hyperexcitability, seizures, and memory deficits. We will pursue the following Aims, Aim1: To characterize complement activation and associated responses in a mouse model of SE and TLE;
Aim2 : To determine the contribution of SE-induced C3 activation to neuronal and synaptodendritic changes in the hippocampus in a mouse model of TLE;
Aim3 : To determine the contribution of SE-induced C3 activation to seizures and hippocampal-dependent memory deficits in a mouse model of TLE. This study will provide a strong framework for understanding the phagocytic role of the innate immune complement system and microglia in the SE-induced generation of epileptic circuits. Our scientific discoveries are likely to provide evidence for the potential therapeutic value of directly modulating the complement cascade to attenuate seizures and cognitive comorbidities in epilepsy. Importantly, because FDA- approved complement inhibitors are currently being used for immunological illnesses in humans, our study may provide evidence to fast track the repurposing of these drugs for their use in epilepsy. 1
Epilepsy is a seizure disorder that is often comorbid with cognitive deficits. Currently available antiepileptic drugs only help suppress seizures in 70-80% of epileptic individuals and do not help with intellectual comorbidities. Thus, the objective of the proposed research is to determine how complement-mediated phagocytic signaling and microglia may contribute to underlying causes of epilepsy and may be potential therapeutic targets.
