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.
Highlights
Kleefstra Syndrome (KS, OMIM#610253) is a rare syndromic form of intellectual disability (ID) associated with autistic features (Kleefstra et al 2005, 2012; Koemans et al 2017; Vermeulen et al 2017), caused by haploinsufficiency of the Euchromatic Histone Methyltransferase 1 (EHMT1) gene
We generated a timeline of P V+ neuron maturation, measuring two maturation markers, Parvalbumin (PV) and Perineuronal Nets (PNNs) in cortical layers 2/3 and 4
In all three sensory cortical areas, we found a reduction of PV+ developmental markers in layer 4 at P14
Summary
Kleefstra Syndrome (KS, OMIM#610253) is a rare syndromic form of intellectual disability (ID) associated with autistic features (Kleefstra et al 2005, 2012; Koemans et al 2017; Vermeulen et al 2017), caused by haploinsufficiency of the EHMT1 gene. We previously reported hyperexcitability in Ehmt1+/− hippocampal excitatory neurons (Frega et al 2020) as well as deficits in evoked excitatory transmission in auditory cortex (Frega et al 2019). Those excitatory phenotypes are broadly replicated in cultured neurons derived from both rodents and human KS patientderived iPS cells (Frega et al 2019; Martens et al 2016). Ehmt and its homolog Ehmt co-regulate activity-dependent gene
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