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.