NETWORK MECHANISMS OF EPILEPTOGENESIS IN A MOUSE MODEL OF HCN1 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES

Developmental and Epileptic Encephalopathies (DEEs) are severe disorders where cognitive functions are impaired by abnormal brain development and seizures. This study investigates the network mechanisms underlying DEEs associated with de novo pathogenic variants in HCN1 encoding hyperpolarization-activated and cyclic nucleotide-gated cation channels. We generated a knock-in mouse model of the human gain-of-aberrant-function HCN1p.G391D variant (Hcn1^G380D/+, HCN1-GD), which exhibits a severe phenotype in both humans and mice, including spontaneous tonic-clonic seizures, motor hyperactivity, and cognitive deficits.
To investigate the network mechanisms underlying epileptogenesis in this mouse model, we performed long-lasting in vivo single-channel telemetry recordings and multichannel depth recordings in the somatosensory cortex and hippocampus. Neonatal and infant mice (P6-P14) were recorded in a stereotaxic setup using Neuronexus electrodes. Head-fixed adult animals (>10 weeks) were recorded in the Mobile HomeCage (MHC) using high-density Neuropixels electrodes combined with parallel video acquisition and movement tracking.
Recordings from neonatal and infant HCN1-GD mice showed spontaneous electrographic seizures in the hippocampus and/or cortex already at P6, indicating an early postnatal onset of epileptogenesis. Adult HCN1-GD mice showed state- and region-specific changes in hippocampal network activity, especially a reduction in gamma power across hippocampal layers during locomotion and lower CA1 single-unit firing rates, supporting the hypothesis of impaired interneuron function in HCN1-GD mice. Polysomnography results showed that mutant mice exhibit increased wakefulness compared to wild-type controls, particularly near the dark/light transition. These sleep disturbances could safely be treated with GABA-A receptor mimetics.