Neurobehavioral Impacts of the Autism Risk Gene, WAC: Studies Involving C. elegans and Mice.

Authors

Napissara Boonpraman, Da-Woon Kim, Elena Tislerics, Janki Barot, Dariangelly Pacheco-Cruz, Nathan C Kuhn, Daniel Vogt, Shreesh Raj Sammi

Published in

Molecular neurobiology. Volume 63. Issue 1. Jun 05, 2026. Epub Jun 05, 2026.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a broad spectrum of behavioral impairments. While multiple genetic and environmental factors are attributed to its cause, biological underpinnings are still poorly understood. The WAC gene has been primarily linked with DeSanto-Shinawi syndrome, a rare neurodevelopmental disorder. Due to overlapping manifestations, studies on WAC gene and its potential role in ASD have recently gained traction. This study elucidates effects of WAC deletion and characterizes the findings and mechanisms vis-à-vis relevant neural aberrations in ASD. Mutant Caenorhabditis elegans (wac-1.1^-/- and wac-1.2^-/-) showed enhanced acetylcholine-associated behavior, as indicated by the aldicarb assay, without any alteration in acetylcholine levels or acetylcholinesterase activity. Upon further investigation, we found that the elevated cholinergic transmission resulted from increased activity of nicotinic acetylcholine receptors (nAChRs). Additionally, we observed reduced motility and dopamine-associated behaviors. Several key genes were upmodulated including lev-1. Notably, lev-1 RNAi did not alter the enhanced cholinergic transmission, suggesting an involvement of multiple players in enhanced cholinergic signaling. Upon further validation in cortical tissue of Wac^+/- mice, no significant difference in CHRNA7 expression was observed compared with WT controls. Although genetic compensation and expression variation in Wac^+/- mice and wild-type mice respectively was observed, in general, an inversely proportionate correlation between Wac mRNA expression and CHRNA7 levels was observed. Overall, these studies indicate alterations in multiple neurotransmitter-associated behaviors result from WAC-gene deletion. Our findings are a step forward in addressing informational gaps with respect to the WAC and ASD.

PMID:
42247028
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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