INVESTIGATING THE PACEMAKING ROLE OF HCN1 DURING CORTICAL DEVELOPMENT

Spontaneous patterns of neuronal activity emerge in the brain as early as the embryonic stages and -together with genetic programs and environmental cues - orchestrate the complex development of the brain, including the cerebral cortex. Among these patterns, cortical calcium waves, are thought to play a key role in neurogenesis, cell migration, proliferation and maturation. While pacemaker neurons have been proposed as initiators of these waves in many brain regions, the molecular regulators of this intrinsic activity in the developing cerebral cortex remain poorly understood. Through an integrated single-cell molecular and functional analysis, we identified the voltage gated ion channel HCN1 as a prominent candidate for modulating intrinsic activity. While HCN1 is known to be involved in the pathogenesis of epilepsy, its role in governing early network dynamics at the subpopulation level during cortical development is not well characterized.
Here, we show that Hcn1 critically shapes the developing cerebral cortex both at morphological and functional level. Using a subtype-specific conditional knockout mouse model, we dissected the contribution of Hcn1 in defining key developmental features of cortical neuronal subtypes through transcriptomic and morphological analyses. Combining two-photon calcium imaging recordings in cortical brain slices and in vivo analyses from early postnatal mice, we unveiled the role of Hcn1 in early cortical dynamics. These findings highlight the importance of ion channel composition in defining the fate of developing cortical neuron subtypes within the neural networks. In this context Hcn1 represents a key determinant, potentially contributing to developmental and epileptic encephalopathies (DEEs) when mutated.