Taken together, these two reports advance our understanding of the role of HCN channels, and in particular HCN1, in epilepsy. The status epilepticus–induced HCN channelopathy following either pilocarpine or kainate predisposes neurons to both intrinsic and network hyper-excitability by virtue of loss of Ih. Ih may curtail membrane excitability and oppose the spread of excitatory synaptic input from distal dendrites; diminution of these constraints likely supports ongoing hyperexcitability and hypersynchronous neuronal firing. As demonstrated in these reports, discrete and specific gene alterations, involving both transcriptional and nontranscriptional mechanisms, likely promote a long-lasting epileptic state. Dissection of the molecular mechanisms involved in Hcn1 gene expression could provide a novel avenue for therapeutics.
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