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

Kim, Young Jin; Khoshkhoo, Sattar; Frankowski, Jan C.; Zhu, Bingyao; Abbasi, Saad; Lee, Sun Young; Wu, Ye; Hunt, Reid

doi:10.1016/j.neuron.2018.09.049

Cited by 64 publications

(57 citation statements)

References 64 publications

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“…Other work has shown that the TSC1-mTOR pathway, which has been implicated in autism, normally represses inhibitory synapses onto excitatory neurons, such that deficiency of Tsc1 leads to decreased inhibition and network hyperexcitability [58]. Mice lacking CHD2, a chromatin remodeling and autism risk gene, had fewer cortical and hippocampal interneurons, and a reduction in miniature IPSC frequency; the mutants' cognitive phenotype was partially rescued by interneuron transplantation [59]. Finally, a large body of work has shown that Rett syndrome, which involves some autism-like features, includes deficits in inhibitory interneuron development and function [60], and that many abnormal behaviors in mice are driven by the loss of MeCP2 specifically in interneurons [61].…”

Section: Altered E-i Balance In Mouse Models Of Autism (Asd)mentioning

confidence: 99%

Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

2019

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In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field's increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.

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Section: Altered E-i Balance In Mouse Models Of Autism (Asd)mentioning

confidence: 99%

Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

2019

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“…Further, observations in human stem cell-derived models (e.g., organoids) will be key to identify species-specific alterations that define the unique features of social behavior in humans. CHD2 proliferation KO mice [189] PTEN survival KO mice [193] TBR1 lamination KO mice [70,77] Author…”

Section: Resultsmentioning

confidence: 99%

Linking Autism Risk Genes to Disruption of Cortical Development

Garcia‐Forn

Boitnott

Akpinar

et al. 2020

Cells

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Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

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“…were enriched for various RNA-related GO categories (Supplementary Table 1). Notably, changes in E13.5 embryo were significantly anti-correlated with those in E13.5 medial ganglionic eminence (MGE) of Chd2 +/mice 22 (Spearman R=-0.27, P<10 -100 ). Milder anticorrelation was observed between dysregulation in the Chaserr +/adult brain and the Chd2 +/adult hippocampus 22 (R= -0.11, P= 8.8×10 -47 ).…”

Section: Relative Expressionmentioning

confidence: 99%

“…Notably, changes in E13.5 embryo were significantly anti-correlated with those in E13.5 medial ganglionic eminence (MGE) of Chd2 +/mice 22 (Spearman R=-0.27, P<10 -100 ). Milder anticorrelation was observed between dysregulation in the Chaserr +/adult brain and the Chd2 +/adult hippocampus 22 (R= -0.11, P= 8.8×10 -47 ). Hundreds of genes were dysregulated in the Chaserr -/-Chd2 m/m mEFs compared to WT mEFs from the same pregnancies, and these changes are likely due to Chd2 loss-of-function, as there was no correlation between these changes and the changes in Chaserr -/-mEFs (Spearman R=-0.003 P=0.68, Fig.…”

Section: Relative Expressionmentioning

confidence: 99%

Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability

Rom

Melamed

Goldrich

et al. 2019

Preprint

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Genomic loci adjacent to genes encoding for transcription factors and chromatin remodelers are enriched for long non-coding RNAs (lncRNAs), but the functional importance of this enrichment is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaserr, a highly conserved lncRNA transcribed from a region near the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaserr in mice leads to early postnatal lethality in homozygous mice, and severe growth retardation in heterozygotes. Mechanistically, loss of Chaserr leads to substantially increased Chd2 mRNA and protein levels, which in turn lead to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaserr production represses Chd2 expression solely in cis, and that the phenotypic consequences of Chaserr loss are rescued when Chd2 is perturbed as well.Targeting Chaserr is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals. excluded in this model. A different model for Chd2 loss-of-function was recently created by the International Mouse Phenotyping Consortium, where exon 3 was replaced by a lacZ cassette and a stop signal 18 . No significant changes in mortality and aging were reported for these mice, but they exhibit slightly decreased body weight and length, skeletal abnormalities, an abnormal bone structure, decreased fat amount and bone mineral density, and abnormalities in blood composition, such as decreased erythrocyte cell number, hemoglobin content, and mean platelet volume (http://www.mousephenotype.org/).In humans, CHD2 haploinsufficiency is associated with neurodevelopmental delay, intellectual disability, epilepsy, and behavioral problems (reviewed in 19 ). Studies in mouse models and cell lines also implicate Chd2 in neuronal dysfunction: perturbations of Chd2 affect neurogenesis in the mouse developing cerebral cortex 20 and in human stem cells differentiated to neurons 21 , and loss of a single Chd2 copy leads to deficits in neuron proliferation and a shift in neuronal excitability 22 . Approaches for increasing CHD2 levels may thus have therapeutic relevance. ResultsLncRNAs are spread throughout vertebrate genomes, but have a notable enrichment in proximity to chromatin-and transcription-related genes 2,9 . One such lncRNA, annotated as 1810026B05Rik in mouse (which we denote as Chaserr, for CHD2 adjacent, suppressive regulatory RNA) and LINC01578/LOC100507217 in human (CHASERR), is an almost completely uncharacterized lncRNA, found upstream of and transcribed from the same strand as Chd2 (Fig. 1a). Chaserr has five exons, is polyadenylated, and is a bona fide lncRNA according...

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

Cited by 64 publications

References 64 publications

Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Linking Autism Risk Genes to Disruption of Cortical Development

Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability

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