Group I Metabotropic Glutamate Receptors and Epileptogenesis

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DESCRIPTION (provided by applicant): The development of epilepsy following traumatic brain injury (TBI), stroke, or status epilepticus is a process that involves many mechanisms that provide targets for the prevention of epilepsy. One mechanism that may be important in all of these causes of epilepsy is excessive glutamate release and activation of metabotropic glutamate receptors (mGluRs). We have not yet developed therapies to prevent the development of epilepsy, particularly following TBI, and our proposal evaluates potential prophylactic therapies. The goal of this program is to develop potential treatments to prevent epileptogenesis by altering the effects of mGluR activation. We have found that activation of group I mGluRs with the selective agonist dihydroxyphenylglycine (DHPG) results in long-lasting changes in hippocampal excitability manifest by spontaneously occurring interictal (between-seizures) and ictal (seizure-like) activity. In the past funding period, we have demonstrated that blockade of group I mGluRs can slow kindling, a model of epileptogenesis. Our findings have created new research questions, which we address in the current proposal. Our first hypothesis is that activation of group I mGluRs increases preferentially the recurrent excitatory synaptic network activity and results in persistent epileptiform activity in the CA3 region of the hippocampus. Our first set of specific aims will address changes in synaptic physiology of the CA3 region that follow transient exposure to DHPG. We will: 1) characterize the frequency and amplitude of spontaneously occurring inhibitory postsynaptic currents (IPSCs) and excitatory post synaptic currents (EPSCs) after DHPG exposure and will compare this with control neuronal activity; 2) evaluate spontaneously occurring EPSCs in the absence of inhibition and spontaneously occurring IPSCs in the absence of synaptic excitation; and 3) determine changes in miniature IPSC and EPSC frequency and amplitude that are associated with DHPG exposure. Our second hypothesis is that long-term changes induced by group I mGluRs are the result of production of Homer 1a, a protein up-regulated by seizures, and change in function of group I mGluRs so that a cation current is activated in the absence of glutamate. Our preliminary data indicate that Homer 1 knockout (KO) mice are resistant to the induction of epileptiform by DHPG. We will therefore determine if Homer 1 KO mice develop changes in membrane properties associated with DHPG exposure and will determine if a transduction of the Homer 1 KO mouse with Homer 1a can re-establish the wild type phenotype as relates to the induction of epileptiform activity by DHPG. We argue that the changes we define that occur following DHPG exposure, models what occurs when high concentrations of extracellular glutamate activate mGluRs, and that they represent a therapeutic target to block the development of epilepsy following head trauma, status epilepticus, and recurrent seizures. The results of our experiments will target new therapies for epilepsy and the development of epilepsy, a major morbidity for combat Veterans who have experienced TBI. PUBLIC HEALTH RELEVANCE: Relevance Statement Epilepsy is a common problem in the VA population. We still have not developed prophylactic therapies to prevent epilepsy that follows conditions of increased glutamate release including head trauma, status epilepticus, or stroke. The hippocampus, an area of the brain involved with memory formation, is susceptible to develop epilepsy following brain injuries. Recent findings of the role of traumatic brain injury and mild concussive injury in the development of post-traumatic stress disorder and memory disorders point to the importance of hippocampal dysfunction. These problems may share common mechanisms with the development of post-traumatic epilepsy. The goal of the work proposed is to develop new therapies for conditions that, in part, are a result of increased glutamate release, activation of certain neurotransmitter receptors, and plasticity changes that cause epilepsy and perhaps post-traumatic stress disorder.