Temporal lobe epilepsy - validation of a new animal model

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DESCRIPTION (provided by applicant): Nearly one third of all patients with epilepsy are refractory to current antiepileptic drugs. These patients are often affected by significant adverse effects due to multi-drug treatment and high drug dosage; thus, more efficacious therapies that will improve the patient's quality of life are clearly needed. The discovery of better therapies has been lagging due to a lack of validated animal models that more closely recapitulate the human epileptogenic state. Based on studies of surgically resected hippocampal tissue from patients with medically intractable temporal lobe epilepsy (TIE), we propose here a novel rat model of TLE by chronic, intracerebral infusions of the glutamine synthetase antagonist, methionine sulfoximine (MSO). This model reproduces a prominent feature of the pathology of human TLE, namely a deficiency of glutamine synthetase in the hippocampus. Preliminary results indicate that the MSO-treated animals develop recurrent seizures and several neuropathological characteristics of the human disease. This proposal seeks to further validate the model as a prelude for future testing of novel therapeutic approaches. The following features will be validated: (1) Intracranial EEG recordings will seek to confirm the mesial temporal origin of the seizures and provide information on other important seizure parameters. (2) Neurohistological studies will attempt to map and quantitate the limited damage to the hippocampus and other brain areas. (3) In vivo microdialysis studies will determine whether extracellular levels of glutamate are elevated in the epileptogenic hippocampus, as in human TLE. Relevance to public health: Nearly 800,000 Americans with epilepsy suffer from uncontrolled seizures that cannot be treated with currently available drugs. More effective therapies of epilepsy are therefore needed. This proposal seeks to validate a new animal model that may greatly speed up the search for better therapies against this disorder.