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.
Brain Struct Funct. 2020 Dec;225(9):2701-2716. doi: 10.1007/s00429-020-02149-9. Epub 2020 Sep 25.
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.
EHMT1 基因突变会导致克莱夫斯特拉综合征，这是一种罕见的智力障碍 (ID) 形式，具有强烈的自闭症特征和感觉处理缺陷。抑制性中间神经元的正常发育对于感觉功能至关重要。在这里，我们报告了 Ehmt1 小鼠三个最重要的感觉皮层中 Parvalbumin 阳性 (PV) 中间神经元发育的时间轴。我们发现，在感觉发育早期，PV 神经元成熟出现了迄今为止尚未报道的延迟，而在发育后期则出现了层和区域特异性的可变性。这种延迟的 PV 成熟也反映在 Ehmt1 听觉皮层 GABA 能传递的延迟成熟中，我们发现特定于假定的 PV 突触的 GABA 释放概率降低。结合早期关于 Ehmt1 神经元兴奋性损伤的报道，我们提出 Ehmt1 感觉皮层中兴奋性-抑制性平衡向过度兴奋的转变是由于抑制性成熟早期缺陷的结果。
