The primary interests of this workgroup focus on the pathogenesis and treatment of chronic neurodegenerative diseases, many of which involve alterations in ligand gated ion channels subserving normal CNS function as a result of derangements in peripheral organ function. For example, hepatic encephalopathy (HE) is a neuropsychiatric syndrome accompanying acute or chronic liver failure. It is characterized by personality changes, sleep inversion, generalized cognitive slowing, incoordination and ataxia leading to coma. We determined that a new class of neuromodulators, the fatty acid amides, are elevated in the CSF of patients and animal models of hepatic encephalopathy. The salient member of this family is oleamide, which is has analgesic, anxiolytic and, most importantly, profound hypnotic actions. We found that the behavioral effects of oleamide were suppressed by GABA receptor antagonists, and in mice with targeted deletions of the beta3 subunit. In contrast, other chronic neurodegenerative disorders involve neuronal damage induced by hyperactivation of glutamate-gated ion channels. While this can result from direct activation by glutamate, we recently identified a virus-induced autoimmune syndrome that produces antibodies to the AMPA receptor. These antibodies activate the receptor, and can damage or kill neurons in vitro. The presence of these antibodies is found in other animal models and patients suffering from retrovirus-induced dementia. Finally, a potentially new modality for treating these hyperexcitability states was determined using molecular genetics techniques. Mice transgenically overexpressing the type 1 sulfonylurea receptor were found to be resistant to seizures and neurodegeneration induced by activation of kainic acid receptors. This suggests that gene transfer therapies using the sulfonylurea receptor may be viable methods for treating focal hyperexcitability states.
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