Germline Chd8 haploinsufficiency alters brain development in mouse

Abstract

Summary The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency on brain development.

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice

“…In order to determine whether genotype‐dependent changes in dendritic morphology are associated with changes in behavior, we used the three‐chambered social approach task to assess social behavior in juvenile mice of each genotype. This test was chosen because it is a simple, automated and standardized assay that can be used with juvenile animals . Mice were initially allowed to explore the empty left and right chambers during a 10 minutes habituation period.…”

“…The three‐chambered social approach was conducted as described previously . Animals were moved to the room 1 hour prior to testing.…”

Observational fear behavior in rodents as a model for empathy

“…Deletions or copy number variations of the neurexin genes ( NRXN1 and NRXN3 ) were directly implicated as genetic risk factors for ASD . Similarly, the Chd gene family and dysregulated neuronal Ca 2+ signaling via L‐type Cav1.2 are also known to be associated with autism . Disturbance of empathy is a salient feature of ASD.…”

Dysregulation of autism-associated synaptic proteins by psychoactive pharmaceuticals at environmental concentrations

“…Due to many genetic factors such as CNV deletions, mutations, allelic exclusion, or epigenetic silencing, the expression of synaptic proteins may be altered. This alteration in the level of synaptic proteins leads to the formation of abnormal neuronal circuits, which is considered to be one of the potential mechanisms underlying ASD [3, 4]. Could psychoactive pharmaceuticals, at environmentally relevant concentrations, dysregulate the expression of key synaptic proteins that further disturb the process of synaptogenesis?…”