Abstract
CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.
Highlights
Cultured neuronal or in utero knockdown of Chd8, with stronger expression in neurons than in glia in humans and mice, suppresses neuronal morphogenesis and radial and callosal migration in the neocortex (Xu et al, 2018). These results suggest that CHD8 promotes brain growth and differentiation and that the macrocephaly induced by heterozygous CHD8/Chd8 mutations may not represent a consequence of disinhibition
Using mice created by crossing the Emx1-Cre line with Chd8fl/fl mice, we found that Emx1-Cre-driven, conditional homozygous knockout of Chd8 restricted to neocortical glutamate neurons with a dorsal telencephalic origin leads to a near-complete loss of neocortical structures
These mice show largely normal auditory functions and partly impaired visual and motor functions but enhanced whisker-related somatosensory cortical function. These changes involved fast and stronger thalamic neuronal activity, revealed by functional magnetic resonance imaging (MRI) and calcium imaging, as well as increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons, which are known to regulate somatosensory processing. These results suggest that CHD8 critically regulates neocortical development and that neocortical loss has distinct impacts on behaviors and sensory-motor functions
Summary
CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler that critically regulates embryonic development and is strongly associated with neurodevelopmental brain disorders, including autism spectrum disorders (ASDs), accounting for $0.5% of ASD cases (Barnard et al, 2015; Bernier et al, 2014; Neale et al, 2012; O’Roak et al, 2012a, 2012b; Sanders et al, 2012; Yasin et al, 2019). Whether the macrocephaly in humans (Barnard et al, 2015; Bernier et al, 2014; O’Roak et al, 2012b; Yasin et al, 2019) and mice (Bernier et al, 2014; Gompers et al, 2017; Jung et al, 2018; Katayama et al, 2016; Platt et al, 2017; Suetterlin et al, 2018; Sugathan et al, 2014; Zhao et al, 2018) induced by heterozygous Chd mutations reflects normal CHD8 functions, namely suppression of normal brain growth, remains unclear because homozygous deletion of the ubiquitously expressed Chd leads to early embryonic lethality in mice through massive apoptosis (Nishiyama et al, 2004, 2009) Along this line, it is interesting to note that CHD8 promotes proliferation and differentiation of neural precursors during brain.
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