Investigation of the in vivo function of excitatory neuronal CHD8

Abstract

Chd8fl/fl mice survive after adult stage. Abnormal morphology showed in these mice caused by apoptosis of differentiated or differentiating neurons during cortical development (E12.5). These mice showed abnormal behaviors in adult stage such as hyperactivity, anxiolytic behavior and increased social interaction, suggesting behavioral disinhibition. Unexpectedly, they displayed normal visual, auditory, olfactory, pain sensing function and partial impairment of motor function. In more complex visual task and fMRI results showed that these mice only could conduct simple visual tasks using light sensing and light movement function by superior colliculus (SC). In addition, these mice showed enhanced whisker-related somatosensory function and these enhancement related to increased thalamic activity with fast activation/inactivation kinetics revealed by 15.2-Tesla fMRI. Furthermore, VPM neurons of these mice showed increased intrinsic excitability and inhibitory inputs from thalamic reticular nucleus (TRN) which receive inputs from cortex to ventral posteromedial nucleus (VPM) were reduced in these mice tested by sIPSC, suggesting weakening of feedback loop circuit of somatosensory pathway. These results suggest the apoptotic role of excitatory neuronal CHD8 in neurodevelopment, and eliminated neocortical structures directly and indirectly causes variety of impacts in mouse behaviors.

CHD8 is a member of chromatin remodeler, which implicated in autism spectrum disorders. CHD8 also well known by its various binding partners. Although many studies investigated heterozygous Chd8 deletion model mouse or conducted patient-base genome analysis, the in vivo function of CHD8 still unclear. However, it is difficult to investigate the function of CHD8 because homozygous Chd8 deletion in mice shows embryonic lethality. To solve these problems, I created conditional knockout mice of Chd8 by crossing neocortical glutamatergic neuronal cre line, Emx1-Cre, which originated from dorsal telencephalon. This Chd8 deletion caused elimination of neocortical structure, Emx1-Cre