Grant: Project Grant

Our goal is to control the biological processes that occur in the brain after an initial insult (e.g., status epilepticus, SE) and lead to focal epileptic disorders such as mesial temporal lobe epilepsy (MTLE), the most common type of adult refractory epilepsy. To this end, we will use a rodent model that recapitulates many of the features of the human condition, including an initial brain insult (i.e., a pilocarpine-induced SE) followed by a seizure-free, latent period before the recurrence of spontaneous focal seizures. Established experimental evidence along with preliminary data obtained in our laboratories have led us to hypothesize that the transient decrease in neuronal excitability that follows the initial SE, induces homeostatic synaptic plasticity (HSP). HSP, which allows neurons to normalize their firing without changing synaptic input strength, may, under pathological conditions such as those following SE, cause adaptive processes leading to spontaneous seizures once the post-SE depression is over. HSP is modulated by the glia-released pro-inflammatory cytokine tumor necrosis factor-alpha (TNF). Therefore, we will: (i) identify the dynamic changes in excitability occurring in mice shortly after a pilocarpine-induced SE; (ii) establish whether the changes in excitability occurring during this latent period are modulated by TNF as HSP does; (iii) prove that augmenting or decreasing TNF function during the latent period modifies the establishment of the epileptic condition; (iv) control the establishment of the epileptic condition by rescuing post-SE hypoexcitability (and thus reducing HSP) with optogenetic activation of CA3, CamKII-positive, principal cells. We believe our studies to be fundamental for identifying new pharmacological strategies for preventing the development of MTLE and, potentially, of other focal epileptic disorder such as post-traumatic epilepsy.