EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas.

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.