PATHOPHYSIOLOGY OF CA2 IN HCN1-G380D MICE: A MODEL OF DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders frequently caused by pathogenic variants in ion channel genes that disrupt neuronal excitability and induce cognitive deficits. Mutations in HCN1, encoding the hyperpolarization-activated cyclic nucleotide–gated channel 1, represent a recurrent cause of DEE, with many variants producing gain-of-function effects on the Ih current these channels generate, resulting in a spectrum ranging from early infantile epileptic encephalopathy to milder epilepsy with cognitive or behavioral impairment. HCN1 is highly expressed in hippocampal pyramidal neurons, including the CA2 subregion, a circuit node essential for social memory and a potential source of seizure generation. This work focuses on a knock-in mouse model replicating a de novo sequence variation in the human HCN1 voltage-gated channel gene, p.G391D(Hcn1G380D/+ in mouse), associated with severe drug-resistant neonatal-onset epilepsy. Here, we examined whether and how this variant affects CA2 excitability and CA2-dependent social behaviors. HCN1-G380D mutation leads to a large loss-of-function decrease in Ih amplitude, with a concomitant reduction in Ih-dependent voltage sag in response to hyperpolarizing current steps. In parallel the residual Ih current shows a gain of function due to the generation of a steady leak-like current. This aberrant channel behavior leads to chronic membrane depolarization and a marked increase of neuronal firing in CA2 pyramidal neurons. HCN1-G380D mice show impaired social memory and increased social aggression compared to wild types, phenotypes compatible with CA2 dysfunction. Understanding how HCN1 mutations perturb CA2 microcircuits suggest a novel mechanism underlying DEE and identify circuit-level targets for precision therapeutic intervention.