Contribution of the Cerebellar Cortex in Absence Seizure Formation in P/Q type Calcium Channel Mouse Models

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Absence epilepsy is one feature of idiopathic generalized epilepsy (IGE), which accounts for 3-4% of all epileptic seizure disorders. Absence seizures, also known as petit mal seizures, are commonly characterized as an abrupt loss of consciousness and behavior arrest for several seconds accompanied by 3-4 Hz spike- and slow-wave discharges on electroencephalograms. However these seizures can lasts up to minutes in atypical absence epilepsy individuals. Although the etiology of IGEs can be complex, one specific type of IGE, childhood absence epilepsy, has been linked to mutations in several ion channels and in particular the P/Q-type calcium channel (Cav2.1). Spontaneous mutations in the P/Q type channel in mice have provided an essential tool for understanding the networks contributing to absence epilepsy. However more genetic tools are necessary to identify specific cellular and molecular pathways involved in absence epilepsy to provide better therapeutic options for suffering individuals. We established a mouse model for elucidating the cell-type specific function of P/Q type channels and demonstrated the functional and developmental role of the P/Q type channel in Purkinje and granule cells in the cerebellum. In these studies we found that the postnatal loss of the P/Q type calcium channels from either Purkinje or granule cells from the cerebellum was sufficient to cause ataxia, dyskinesia and absence seizures in mice. We will now use these established mouse lines to investigate the contribution of specific cerebellar neurons in the initiation and development of absence seizures. In addition we will develop optogenetic tools to identify the second messenger pathways involved in absence seizure formation, which may be useful therapeutic tools to eliminate absence seizures in humans.