UC Riverside

Epilepsy is one of the most common neurological disorders and is characterized by the occurrence of unprovoked seizures. Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures. Unfortunately, some patients will develop refractory epilepsy that is pharmaco-resistant to current antiepileptic drugs (AEDs). Current AEDs work primarily by targeting neurons directly by inhibition of glutamatergic excitatory neurotransmission or enhancement of GABAergic inhibitory neurotransmission. Non-neuronal targets are an attractive alternative approach to treat epilepsy with potentially fewer deleterious effects. Neuronal hyperexcitability is a major contributor to epilepsy but increased evidence suggests that changes in astrocytic glutamate transporters can contribute to the development of epilepsy. This proposal aims to examine the cellular and molecular mechanisms associated with glutamate transporter dysregulation and their potential as a therapeutic target in epilepsy. I hypothesize that astrocytic glutamate transporter dysregulation contributes to the development of epilepsy and therefore can be targeted for the attenuation of epilepsy. Changes in astrocytic glutamate transporters were evaluated post-kainate induced status epilepticus. Additionally, post-translational modifications (PTMs) of these transporters that have previously been determined to cause both mislocalization and dysfunction of glutamate transporters in other models of neurological disease including SUMOylation, ubiquitination and palmitoylation were examined. For the first time, whether glutamate transporter modulation reduces seizures and attenuates pathological changes observed in the IHKA model of TLE using an AAV-Gfa2-GLT1-cHA viral vector and neuregulin (NRG-1) treatment was investigated. Finally, real-time glutamate spike activity to identify whether marked glutamate spike patterns can be used to predict epileptiform activity in epileptogenesis was examined. The main findings from these studies are: 1.) Synaptosomal GLT-1 protein is downregulated at a critical time point in epileptogenesis; 2.) Overexpression of GLT-1 in astrocytes delays neuronal death and granular cell dispersion in epileptogenesis; 3.) Overexpression of GLT-1 suppresses electrographic seizures and large behavioral seizures in epileptogenesis; 4.) Exogenous NRG-1 treatment induces upregulation of glutamate transporter EAAC1 and bi-hemispheric neuroprotection in epileptogenesis; and 5.) Glutamate peak events are increased in the epileptic brain and could be used as a biomarker in TLE.