Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice.

Abstract

Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability. In the case of fragile X syndrome, early preclinical studies suggest that BKCa channels may be a promising treatment target for neurodevelopmental disorders. While BKCa channel dysfunction has been investigated within the context of fragile X syndrome, it is unknown whether interference with BKCa channel function is inductive for deficits in behavioral domains relevant to neurodevelopmental disorders. This represents a critical gap in our knowledge regarding the relationship between BKCa dysfunction and neurodevelopmental disorders. To explore this concept, we used the BKCa channel antagonist paxilline to evaluate the role of BKCa channel function in phenotypes of neurodevelopmental disorders. Here we used adult male C57BL/6J mice and a series of behavioral paradigms which assessed anxiety-like behavior, locomotor activity, social behavior, and repetitive self-grooming. We found that acute inhibition with paxilline induced a specific social deficit, but not anxiety-like behavior, or hyperactivity. These findings demonstrate proof-of-concept regarding a relationship between BKCa channel impairment and social behavior. Although this is a limited characterization of the BKCa channel in autistic-like behaviors, it provides evidence for this link. Future studies which examine the effective dose range of paxilline and exhaustive assays of behavior relevant to neurodevelopmental disorders will be needed to delineate the parametric space of the paxilline effect, particularly during critical periods of development, and its potential for therapeutic use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).