GENES AND CHANNELS

Inherited ion channel disorders contribute to one third of known mendelian epilepsies. Typically, the effect of the mutation upon membrane excitability and firing properties is known, yet the diffuse pattern of mutant gene expression fails to predict the emergent seizure type. In collaboration with R. Brenner and R. Aldrich, we recently identified one mechanism for selective network vulnerability and seizures in the temporal lobe.

Dentate granule cells integrate and filter synaptic input from entorhinal cortex and transmit this information to downstream hippocampal neurons. Evidence from several models indicates that reduced synaptic inhibition impairs this granule cell 'gate', facilitating epileptogenesis. Three calcium-activated potassium channel subtypes contributing to afterhyperpolarization in brain. One gene, slo, encodes the pore-forming α subunit of BK (maxi K) channels that open rapidly in response to cytosolic calcium. While BK channels are diffusely expressed in the CNS, their accessory β subunits display distinct subpatterns of expression. The β4 subunit (KCNMB4) shows intense expression in dentate granule cells. To examine its role in hippocampal excitability, we deleted this subunit gene. In vitro studies of mutant mice revealed granule cell hyperexcitability, with decreased AHPs and reduced spike frequency adaptation, producing prolonged repetitive firing upon intracellular depolarization. Consistent with a breakdown of the dentate filter, videoEEG recordings of adult mutant β4-/- mice showed spontaneous seizures emanating from the hippocampus and temporal cortex. The coordinate expression of this mutant gene and the seizure type demonstrates that defects in intrinsic membrane excitability as well as synaptic disinhibition within the dentate gyrus lead to breakdown of the granule cell gate control of hippocampal pyramidal circuitry. The β4-/- mouse provides a novel single gene model of non-convulsive epilepsy suitable for the exploration of seizures of temporal lobe origin.