Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors

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. [Display omitted] •Cortical excitatory neuronal Chd8 deletion eliminates cortical structures in mice•Chd8 deletion distinctly alters cognitive behaviors and sensory-motor functions•Chd8 deletion enhances whisker-related somatosensory function and thalamic activity•Chd8 deletion alters thalamic VPM neuronal excitability and synaptic transmission Kweon et al. report that Chd8 deletion restricted to cortical excitatory neurons in mice leads to near-complete elimination of cortical structures. This accompanies changes in cognitive behaviors and sensory-motor functions, including enhanced whisker-related somatosensory function. Thalamic neurons show strong responses upon whisker stimulation involving altered neuronal excitability and synaptic transmission.