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

Cell Reports

Geun Ho Im¹  Seong-Gi Kim²  Hyun Kim²  Hyun-Ji Shim²  Jason P. Lerch³  Won Beom Jung³  Jia Ryoo³  You-Hyang Song⁴  Haram Park⁴  Lily R. Qiu⁴  Yeonsoo Choi⁴  Won-Suk Chung⁵  Seung-Hee Lee⁵  Eunjoon Kim⁶  Hwajin Jung⁶  Hogyeong Do⁶  Joon-Hyuk Lee⁶  Hanseul Kweon⁶  Daesoo Kim⁷  Esther Yang⁷  Jacob Ellegood⁷ 

[1] Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, Korea;Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford OX3 9DU, UK;Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon 16419, Korea;Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea;Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul 02841, Korea;Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea;Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON M5T 3H7, Canada;

关键词: autism;    CHD8;    neurodevelopment;    cortex;    somatosensory;    whisker;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown