Altered neocortical gene expression, brain overgrowth and functional over-connectivity inChd8haploinsufficient mice

Abstract

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display subtle brain hyperplasia shortly after birth, hypertelorism, early motor delay, pronounced hypoactivity and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid-gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the down-regulated transcripts. Restingstate functional MRI identified increased synchronised activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioural phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring result in distinctive anomalies in functional brain connectivity in Chd8 +/-mice. Human imaging studies have consistently found evidence for changes in functional connectivity in ASD cohorts, most commonly long-range under-connectivity. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/143552 doi: bioRxiv preprint first posted online May. 29, 2017; 3 SIGNIFICANCE STATEMENTDe novo mutations in the chromatin remodeling factor CHD8 cause ASD with high penetrance, making CHD8 one of the leading ASD candidate genes. We established a Chd8 heterozygous mouse model that recapitulates anatomical phenotypes seen in patients with CHD8 haploinsufficiency and displays a unique complement of behavioural phenotypes.Increased functional connectivity observed in cortical and hippocampal areas suggests that neuropsychiatric phenotypes associated with CHD8 deficiency may be the result of distinct connectivity changes. Transcriptomic analyses highlighted dysregulation of axon guidance genes as a possible underlying mechanism. Together, our data suggest that CHD8 haploinsufficiency represents a distinct ASD subtype characterised by a unique set of anomalous behaviours, including increased responsiveness to social stimuli, and functional connectivity changes in mice.not peer-reviewed)

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination

“…Spontaneous Motor Activity and Reward Learning are Unchanged in Chd8 +/E31T Mice, but These Mice Perform Better than Wild-types at the Rotarod Task There have been conflicting reports of previous lines of Chd8 mice in their spontaneous motor activity in the open field. Some groups have reported hypoactivity in their lines [Jung et al, 2018;Platt et al, 2017;Suetterlin et al, 2018], whereas others have reported no changes in activity [Gompers et al, 2017;Katayama et al, 2016]. Our mice did not display hypoactivity and instead trended toward hyperactivity in the open field, although this difference was not significant (Figure 4(a)).…”

“…The gene structure of Chd8, the location of mutations in mouse models previously generated in the literature [Gompers et al, 2017;Jung et al, 2018;Katayama et al, 2016;Platt et al, 2017 ;Suetterlin et al, 2018], and the targeting vector used for the current study are depicted in Figure 1(a). Consistent with previously published lines, homozygous mutants were embryonic lethal, but heterozygous mutants, which are haploinsufficient for the full-length protein (Figure 1(b)) were used for subsequent behavioral phenotyping.…”

“…Self-grooming is often elevated in mouse models of ASD and is thought to represent a repetitive behavior [Lewis, Tanimura, Lee, & Bodfish, 2007]. However, most lines of Chd8 mutant mice are no different than wild-type mice on self-grooming assays [Gompers et al, 2017;Katayama et al, 2016;Platt et al, 2017;Suetterlin et al, 2018]. One line of Chd8 mutant mice has elevated rates of selfgrooming, but only under certain conditions: it only occurs after prolonged social isolation and it only occurs in male mice [Jung et al, 2018].…”

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

“…66,67 Disruption of the homologous gene (Chd8) in animal models has demonstrated that the resulting protein plays a key role in very early neurodevelopmental processes, including neuronal proliferation and differentiation 68,69 as well as cell adhesion and axon guidance. 70 On the other hand, MAGMA competitive gene-set analysis revealed a significant enrichment of discordant genes for functions including synaptic transmission and postsynaptic density, as well as membrane depolarization and voltage-gated cation channel activity. Although these processes have been commonly associated with both schizophrenia 33,35 and cognitive phenotypes, 20,21,24,[71][72][73][74] our study is the first to demonstrate that these synaptic mechanisms operate in a surprising manner: the same synaptic functions that increase risk for schizophrenia also serve to enhance educational attainment.…”

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

“…Interestingly, a significant number of ASD genes have been shown to play important roles in gene expression regulation, including transcriptional factors, chromatin remodeling factors and other types of epigenetic regulators, such as CHD8, FMR1, MECP2, and so on [Alonso-Gonzalez, Rodriguez-Fontenla, & Carracedo, 2018;De Rubeis et al, 2014]. Accordingly, numerous loss of function animal models were generated, especially the mouse models, to recapitulate the disease phenotypes and to explore the underlying molecular mechanisms [Araujo et al, 2017;Arbogast et al, 2018;Caubit et al, 2016;Celen et al, 2017;Cheng et al, 2018;Gabel et al, 2015;Harrington et al, 2016;Huang et al, 2018;Jung et al, 2018;Kong et al, 2014;McGill et al, 2018;Prilutsky et al, 2015;Provenzano et al, 2016;Raman et al, 2018;Scandaglia et al, 2017;Sgado et al, 2013;Suetterlin et al, 2018;Zhao, Goffin, Johnson, & Zhou, 2013]. With these models, RNA-Seq or microarray experiments have been performed in various brain regions to identify the downstream targets of the corresponding ASD genes.…”