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Deciphering the role of CAPZA2 in neurodevelopmental disorders: Insights from mouse models

ABSTRACT: Intellectual disability affects 1%-3% of the global population, with many unidentified genetic causes. This study investigates the role of CAPZA2, an actin cytoskeleton regulator, in neurodevelopmental disorders using CAPZA2 heterozygous knockout (CAPZA2+/−) and heterozygous point mutant (CAPZA2c.G776T/+) mice. CAPZA2+/- and CAPZA2c.G776T/+ mice demonstrated notable decreases in CAPZA2 expression within the hippocampus and prefrontal cortex (PFC), crucial for learning and memory. Interestingly, the reduction of CAPZA2 in CAPZA2c.G776T/+ mice is less than 50%. Behavioral assays revealed that CAPZA2+/- mice exhibited motor dysfunction and anxiety-like behaviors, along with impairments in both spatial and non-spatial memory, accompanied by deficits in social interactions. These phenotypic manifestations were also mirrored in the CAPZA2c.G776T/+ mice, thus validating the genotype-phenotype correlation. Morphological analyses of these gene-edited mice indicated structural synaptic impairments, with increased dendritic spine density, altered spine morphology in the hippocampus, and decreased dendritic complexity in the PFC. Single-cell RNA-seq analysis of hippocampal tissue in CAPZA2+/- mice showed widespread transcriptional dysregulation, affecting neurodevelopment and synaptic function genes. The altered PSD95 and glutamate receptor levels support these findings. These in-sights highlight the gene's essential role in brain development and function, with po-tential implications for understanding and treating neurodevelopmental disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE295653 | GEO | 2025/06/10

REPOSITORIES: GEO

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Project description:Many forms of synaptic plasticity are critically dependent upon production of cGMP to trigger activity-dependent increases in synaptic size and strength. Phosphodiesterase 9A (PDE9A) is a high affinity, cGMP-specific phosphodiesterase with widespread distribution in the central nervous system. Inhibition of PDE9A results in significant accumulation of cGMP in brain tissue and cerebrospinal fluid (CSF) of rodents, and increases CSF cGMP in human volunteers. We hypothesized that chronic exposure to a PDE9A inhibitor, and the associated elevations in brain cGMP could provide a therapeutic benefit to vulnerable synapses chronically exposed to Aβ in transgenic mice over-expressing human mutant amyloid precursor protein (Tg2576 mice). A total of N=20 animals per group of 4 month old Tg2576 mice and non-transgenic littermates (WT) were implanted with Alzet osmotic minipumps to deliver vehicle or the PDE9A inhibitor PF-04447943. Neurobehavioral outcomes were measured as conditioned fear response after 28 days of treatment and subsequently brains were harvested for measurement of Aβ, gene expression profiling or synaptic density as assessed by Golgi staining of dendrites. Dendritic spine density on apical dendrites of CA1 neurons exhibited a small but significant deficit in the density of dendritic spines in vehicle treated Tg2576 mice as compared to WT mice. This deficit was ameliorated by 30 days of exposure to PF-04447943. No significant drug effect was observed in WT mice. No significant effects of drug treatment were observed on Aβ levels in Tg2576 mice. Behavioral analysis of Tg2576 mice showed deficits in fear conditioning as early as 2 months old, and therefore were considered unlikely to be due to the accumulation of oligomeric Aβ. These deficits were not affected by drug treatment. Transcriptional profiles of Tg2576 mice treated with drug compared to vehicle showed evidence of regulation of pathways related to synaptic plasticity and remodeling of the dendritic cytoskeleton, consistent with stabilization of vulnerable spine structure. These data supports the hypothesis that PDE9A inhibition can stabilize vulnerable synapses early in the Alzheimer’s disease process. 4-month old Tg2576 mice and non-transgenic (WT) littermates were implanted with minipumps to deliver vehicle or the PDE9A-inhibitor, PF-04447943, for 28 days. At the end of the study, hippocampus and frontal cortex were dissected from n=8 mice per group, RNA was isolated, and hybridized to Affymetrix 430 2.0 mouse whole genome microarray.

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Deciphering the role of CAPZA2 in neurodevelopmental disorders: Insights from mouse models

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