Grant: Project Grant

Our goal is to control the changes in brain excitability that follow a precipitating event and lead to mesial temporal lobe epilepsy (MTLE); this process is known as epileptogenesis. To this end, we will employ an animal model in which spontaneous seizures start to recur around 5-10 days after a status epilepticus (SE) induced by i.p. injection of pilocarpine; a similar, but more prolonged, seizure-free latent period also occurs in MTLE patients. Previous studies suggest that in rodents the appearance of spontaneous seizures following SE results from the sustained inhibitory control of interneuron excitability that in turn leads to disinhibition of principal glutamatergic cells. Therefore, we hypothesize that the dynamic changes in GABA type A receptor-mediated inhibition occurring in the limbic system after SE can be delayed (and perhaps arrested) by direct or indirect optogenetic stimulation of interneurons, implemented shortly after SE. This hypothesis will be tested by using in vivo EEG recordings along with optogenetic activation of specific types of neurons in the hippocampus and the entorhinal cortex of transgenic mice for up to 14 days after the initial pilocarpine-induced SE. Specifically, we will establish whether: (i) optogenetic direct activation of parvalbumin-positive interneurons in the hippocampus can delay the appearance of the first spontaneous seizure that marks the beginning of the epileptic condition; and (ii) optogenetic activation of CamKII-positive principal (glutamatergic) cells in the entorhinal cortex (which in turn project to the hippocampus activating principal cells and different types of local interneurons) can alter the length of the latent period in a way similar or opposite to what observed with optogenetic activation of parvalbumin-positive interneurons. Data obtained from mice undergoing these two protocols will be compared with those seen in animals implanted with the optogenetic device but not stimulated.