EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas
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ORIGINAL ARTICLE
EHMT1 regulates Parvalbumin‑positive interneuron development and GABAergic input in sensory cortical areas Moritz Negwer1 · Karol Piera1 · Rick Hesen1 · Lukas Lütje1 · Lynn Aarts1 · Dirk Schubert2 · Nael Nadif Kasri1,2 Received: 12 February 2020 / Accepted: 10 September 2020 © The Author(s) 2020
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 P V+ neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed P V+ 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. Keywords Parvalbumin-positive interneurons · Kleefstra syndrome · Gabaergic synapse · Critical period · Cortical development · Autism spectrum disorder · EHMT1
Introduction 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. The EHMT1 protein (also known as GLP or KMT1D) functions as a repressive epigenetic modifier by mono- and dimethylating euchromatic Histone 3 on Lysine 9 (H3K9me1/2; Benevento et al. 2015; Iwase et al. 2017; Shinkai and Tachibana 2011; Tachibana et al. 2005). Mice with a heterozygous loss-of-function mutation Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00429-020-02149-9) contains supplementary material, which is available to authorized users. * Nael Nadif Kasri [email protected] 1
Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, The Netherlands
Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands
2
in the Ehmt1 gene recapitulate the core phenotypes of KS, including low muscle tone, delayed development of sensory modalities and craniofacial abnormalities (Balemans et al. 2010, 2014). Ehmt1+/− mice show a delayed onset of sensory experiences (eye opening) and sensory reaction (acoustic startle response; Balemans et al. 2014), as well as impaired learning and exploration, reduced locomotor activity, and increased anxiety (Baleman
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