Kir2.1 channel dysfunction underlies neurovascular coupling impairment in autism

About This Grant

PROJECT SUMMARY Autism spectrum disorder (ASD) affects an estimated 1 in 36 children (2.8%) in the US and is among the top 10 causes of child disability worldwide. Despite its significant medical and economic burden, current therapeutics are limited and none of the available medications treat the 3 core symptoms of ASD: challenges with communication, social skills, and repetitive behaviors. Many of these therapies are based on research from a neuronal perspective – begging the question of whether other factors may be at play. Of the >800 genes associated with ASD, many are expressed in the cardiovascular system and people with ASD are at an increased risk of developing cardiovascular disease. Spanning >400 miles in the brain, the cerebral vasculature is crucial for proper brain function – facilitating rapid and localized increases in blood flow in response to elevated neuronal activity. This process, termed functional hyperemia (FH), is critical to supply neurons with sufficient oxygen and nutrients to function properly, as the brain does not have its own energy reserves. Our collaborators conducted a foundational study that established endothelial-dependent impaired FH in the 16p11.2 locus deletion (16pDel) mouse model of ASD which was published in Nature Neuroscience. Further, they have identified a compound that rescues endothelial function and behavioral phenotypes in this mouse model. Neuronal, vascular, and molecular mechanisms collectively termed ‘neurovascular coupling’ (NVC) underlie FH, yet these mechanisms have not been examined within the context of ASD. Our previous work has detailed a novel NVC mechanism whereby brain capillaries sense neuronal activity via Kir2.1 channels. Therefore, I aim to characterize Kir2.1 channel function and NVC in 16pDel mice. My preliminary data revealed general Kir2.1 channel dysfunction and impairment in Kir2.1-dependent NVC that is rescued with the compound specified above. However, additional insight to Kir2.1 channel dysfunction and the mechanism by which the compound acts to restore NVC is needed to develop viable therapies from this lens. Through my first aim, I will characterize the cell- and region- specificity of the Kir2.1 channel dysfunction – providing necessary insight to the function of the entire microvascular tree. The second aim will elucidate the mechanism by which this compound exerts its rescue effect. Specifically, I will determine if it enhances Kir2.1 channel function by increasing bioavailability of its crucial cofactor, PIP2. The findings hold promise to not only establish further evidence for the involvement of the cerebral vasculature in neurodevelopmental disorders, but also give mechanistic insight to a novel therapeutic avenue. This will provide foundation for an intriguing new field aimed at understanding the role of cerebral vasculature in cognitive function of young adults.