EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas
Moritz Negwer, Karol Piera, Rick Hesen, Lukas Lütje, Lynn Aarts, Dirk Schubert, Nael Nadif Kasri
Abstract
Abstract Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. Proper development of inhibitory interneurons is crucial for sensory function. Here we report a timeline of Parvalbumin-positive (PV + ) interneuron development in the three most important sensory cortical areas in the Ehmt1 + / − mouse. We find a hitherto unreported delay of PV + neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed PV + maturation is also reflected in a delayed maturation of GABAergic transmission in Ehmt1 + / − auditory cortex, where we find a reduced GABA release probability specifically in putative PV + synapses. Together with earlier reports of excitatory impairments in Ehmt1 + / − neurons, we propose a shift in excitatory-inhibitory balance towards overexcitability in Ehmt1 + / − sensory cortices as a consequence of early deficits in inhibitory maturation.