Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory

Highlights

• CHD2 is widely expressed in the embryonic and mature brain

• Gene expression is broadly altered by Chd2^+/−

• Chd2^+/− mice have deficits in neuron proliferation, synaptic function and memory

• Interneuron transplantation rescues memory problems in Chd2^+/− mice

Summary

Considerable evidence suggests loss-of-function mutations in the chromatin remodeler CHD2 contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show that Chd2^+/− mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2^+/− mice, including alterations in neurogenesis, synaptic transmission, and disease-related genes. Deficits in interneuron density and memory caused by Chd2^+/− were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory.