Mechanisms Underlying Maladaptive Organization of Long-range Epileptic Circuits A

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DESCRIPTION (provided by applicant): Clinical cortical stimulation and mapping studies led to the idea that the dysplastic neural networks are functionally integrated and atypically organized. However, the mechanisms for the establishment of aberrant neural networks and atypical brain organization await elucidation. In patient with cortical malformation, sensorimotor region are most frequent in finding polymicrogyri, and seizure onset commonly occurs with or near cortical areas for language and motor function. Motivated by these common clinical features of cortical dysplasia, we modified a neonatal freeze lesion animal model to interrogate how efferent activities in the normal motor cortex (M1), interacts with epileptogenic circuits located within ipsilateral malformed sensory cortex (S1). In our new mice model, optogenetic approaches will be combined with traditional focal freeze lesion, to study interactions between long-range motor cortical projections and local circuits within malformed sensory cortex. We hypothesize that 1) long-range connections from M1 onto interneurons are severely altered in malformed S1 cortex, leading to heightened ictogenesis and propagation. 2) Sensorimotor experiences during critical periods may selectively promote glutamatergic innervation of interneurons; thereby mitigate motor cortex induced seizure in S1. This exploratory grant is directed to provide the first proof of the involvement of long-range motor projection induced ictogenesis in S1, as well as its modulation by innate animal behavior. Understanding how glutamatergic synapses and epileptic activities are modulated by innate sensorimotor experiences during critical period will help development of stimulation-based physical therapy strategies might be used to mitigate or eradicate epilepsy pathology in humans.