LIMBIC EPILEPSY IN TRANSGENIC MICE CARRYING A CA2+ CALMODULIN-DEPENDENT KINASE-II ALPHA-SUBUNIT MUTATION/

Multifunctional Ca2+/calmodulin dependent protein kinase II (CaMK) pho sphorylates proteins pivotally involved in diverse neuronal processes and thereby coordinates cellular responses to external stimuli that re gulate intracellular Ca2+ [Hanson, P, I. and Schulman, H. (1992) Annu. Rev. Biochem. 61, 559-664], Despite extensive study, the impact of th is enzyme on control of the excitability of neuron populations in the mammalian nervous system in situ is unknoull. To address this question , we studied transgenic mice carrying a null mutation (-/-) for the al pha subunit of CaMK. In contrast to wild-type littermates, null mutant s exhibit profound hyperexcitability, evident in epileptic seizures in volving limbic structures including the hippocampus, No evidence of in creased excitability was detected in mice carrying null mutations of t he gamma isoform of protein kinase C, underscoring the specificity of the effect of CaMK. CaMK plays a powerful and previously underapprecia ted role in control of neuronal excitability in the mammalian nervous system. These insights have important implications for analyses of mec hanisms of epilepsy and, perhaps, learning and memory.