Cerebellar gabaergic perturbation in a NDD mouse model
Active Project Grant Awarded Last action
- Award ID
- F31MH144827
- Recipient
-
University Of California, Davis UEI TX2DAGQPENZ5
- Awarding agency
-
National Institute of Mental Health
National Institutes of Health, Department of Health and Human Services
- Obligated
- $43,749
Award facts
- Assistance listing
- 93.242 Mental Health Research Grants
- Completion date 0% complete
- Place of performance
- Davis, CA, USA
Award details come from USAspending.gov.
Description
- Abstract
- Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects more than 2% of the US population. Despite the high prevalence and known genetic causes, lack of understanding of cellular and molecular mechanisms of ASD is a major barrier towards developing effective treatments for this complex disorder. Much of the understanding of the genetic etiology in ASD comes from large scale genome sequencing efforts, which have revealed a growing list of high confidence risk genes. Of these rare but strongly causal ASD risk genes, the chromatin remodeling factor (CRF) chromodomain helicase DNA-binding protein 8 (CHD8) has among the most frequent and highest penetrance for DE novo mutations associated with ASD diagnosis. CHD8 has been broadly characterized as a regulator of neurogenesis and brain development though much remains unknown regarding direct and indirect roles of this protein in specific cell types in the developing brain. Studies of mice with germline heterozygous loss-of-function (LOF) mutations to CHD8 have found behavioral and cognitive deficits, subtle social phenotypes, and macrocephaly, as well as transcriptional, cellular, and molecular pathology relevant to ASD. Most molecular studies into the function of this gene are focused on neurodevelopment in the cortex. And although typically studied in the context of motor function, the cerebellum (CB) plays a central role in higher order cognitive functions and CB dysfunction has been shown to be correlated with ASD and NDD. There have been a few studies on the role of CHD8 in the CB, which have shown requirement for CHD8 for CB development and function. However, previous reports have used conditional knockout approaches rather than the ASD-relevant germline heterozygous state, and largely failed to identify impacts in heterozygous mutant mice in the CB in purkinje neuron (PN) and granule cell progenitor ckos. Preliminary data in our lab found cell type specific transcriptional and functional perturbation to the development of CB gabaergic cell types, including PNS. I hypothesize that the heterozygous CHD8 mutation contributes to ASD pathogenesis through developmental dysregulation of PNS, the only projecting cell type from the CB cortex. Here I propose work to characterize the effect of CHD8 haploinsufficiency on the function and development of PNS using translationally relevant constitutive heterozygous CHD8 mutant mice. In aim 1, I will integrate histology, electrophysiology, and transcriptomics to test whether the composition and function of PN subtypes is altered in CHD8 haploinisufficient mice. In aim 2, I will use single cell transcriptomics to test if gabaergic neurogenesis is altered in the CB ventricular zone. This work will provide a better understanding of the mechanism and effects of decreased CHD8 dosage on a key cell type in the CB. If successful, this proposal will inform future directions for measures to treat underlying pathology and provide a better understanding of the role crfs play in CB neurogenesis and ASD etiology.
Quick answers
Who received award F31MH144827?
F31MH144827 was awarded to University Of California, Davis by National Institute of Mental Health (National Institutes of Health) on February 26, 2027.
How much is award F31MH144827 worth?
$43,749 has been obligated on F31MH144827.
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