Autism spectrum disorders (ASDs) comprise a constellation of symptoms, including impaired social interactions, communication and language deficits, and repetitive behaviors that manifest during early development. Various genetic targets associated with ASDs have been identified, but given the spectrum of symptoms, it has become clear that multiple genes play a part in the disorder. Dysfunction of cortical connectivity is thought to be a hallmark of ASDs, and many of the genes implicated in ASD are involved in synapse formation and function. Although many recent studies have investigated synaptic connections in ASD, the underlying mechanisms are still unknown.
Functional alterations of large-conductance calcium-activated potassium (BK) channels have been linked to intellectual disability and ASD. Interestingly, a recent study showed that fragile X syndrome, one of the best-studied forms of ASD, is linked to alterations in BK channels1. The report showed that loss of FMR1, an RNA-binding protein that controls local protein synthesis in dendrites of neurons, causes excessive action-potential broadening and, thus, elevated levels of neurotransmitter release. FMR1 interactions with the beta4 subunit of the BK channels were shown to underlie this synaptic function. Thus, the BK channels provide a locus for further investigation in the modulation of synaptic communication in ASD.
Laura Schrader and her colleagues at Tulane University will investigate the role of BK channels in ASD-like behaviors in a mouse model of fragile X syndrome. Their specific hypothesis is that BK channel expression is decreased in the FMR1 knockout mouse model, leading to social and cognitive impairments. This project will assess whether social and cognitive impairments in FMR1 knockout mice can be mitigated by early pharmacological activation of BK channels. The team will also investigate the developmental expression and function of BK channels, and the phenotypes exhibited by BK channel modulation.
Results from these studies will help inform our understanding of the role that BK channels play in ASD and other neurodevelopmental disorders, and could suggest BK channels as novel therapeutic targets for these disorders.
References:
1. Deng P.Y. and V.A. Klyachko J. Physiol. Epub ahead of print (2015) PubMed
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
