Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly.

Abstract

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the <i>PAFAH1B1</i> (mouse: <i>Pafah1b1</i>) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of <i>Pafah1b1</i> mutation on the cellular migration, morphophysiology, microcircuitry, and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical 'intermediate spiking (IS)' subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.