The GABA A receptor (GABAR) mediates fast synaptic inhibition in the brain and its dysfunction is implicated in several forms of acquired epilepsy. Heteropentameric GABAR subunit composition plays a role in determining the pharmacology and physiology of the receptor. When pilocarpine is used to induce status epilepticus (SE) in adult rats, spontaneous seizures (SS) later develop and GABAR alpha 1 subunit mRNA levels decrease. However, when SE is induced at P10, animals do not develop SS and show increases in the alpha 1 subunit mRNA levels. It is unclear what factors contribute to modifying the expression of this subunit, and how this change is involved in the development of SS. Investigation into transcription factors that are stimulated by seizures and regulate the alpha 1 subunit may therefore elucidate these mechanisms of epileptogenesis. The cAMP response element binding protein (CREB), which may be activated by SE, is a candidate regulating transcription factor because the alpha one promoter contains its response element sequence.
The aims proposed here will investigate whether: 1) seizures stimulate CREB activity 2) CREB binds to the alpha 1 promoter 3) different CREB activating pathways affect alpha one mRNA levels.
