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Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory
Young J Kim1, Sattar Khoshkhoo2, Jan C Frankowski1
1Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
Abstract:
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.
Insights
Mutations in the CHD2 gene impair brain function, causing neurodevelopmental disorders. This study reveals how CHD2 haploinsufficiency affects neuron development, synaptic function, and memory in mice, offering insights into human conditions.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Loss-of-function mutations in CHD2 are linked to human neurodevelopmental disorders.
- The precise mechanisms by which CHD2 mutations impair brain function remain unclear.
Purpose of the Study:
- To investigate how heterozygous mutations in the chromatin remodeler gene Chd2 affect brain function and neurodevelopment in mice.
- To elucidate the molecular and cellular underpinnings of Chd2 haploinsufficiency-related cognitive deficits.
Main Methods:
- Generated mice with heterozygous mutations in Chd2 (Chd2+/-).
- Assessed neurodevelopmental phenotypes, including neuron proliferation, excitability, and synaptic function.
- Analyzed transcriptional changes, cortical rhythmogenesis, and long-term memory.
- Investigated the role of interneurons via targeted mutation and transplantation.
Main Results:
- Chd2+/- mice showed deficits in neuron proliferation and altered neuronal excitability with impaired excitatory and inhibitory synaptic function.
- Aberrant cortical rhythmogenesis and severe long-term memory deficits were observed in Chd2+/- mice.
- Transcriptional analysis revealed age-dependent alterations in neurogenesis, synaptic transmission, and disease-related genes.
- Reduced interneuron density and memory deficits were linked to Chd2 mutation in inhibitory neurons and could be rescued by transplantation.
Conclusions:
- Chd2 haploinsufficiency disrupts cortical network function by affecting neuron proliferation, synaptic transmission, and interneuron development.
- These findings provide a mechanistic link between Chd2 mutations and neurodevelopmental disorders, highlighting impaired memory as a key phenotype.
- Targeting interneuron function presents a potential therapeutic avenue for Chd2-related cognitive impairments.
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