Enhancing KIR2.1 channel conductance restores capillary–arteriole signaling in a mouse model of autism

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects an estimated 1 in 36 children. Despite extensive investigation into neuronal mechanisms underlying ASD, therapeutics fail to address core symptoms such as difficulties with communication, social skills, and impulsivity – prompting consideration of alternative systems. Interestingly, GWAS studies show that many ASD-linked genes are expressed in the cardiovascular system, and hypoperfusion in brain regions tied to core ASD symptoms has been reported. These findings suggest a potential vascular component to ASD. The brain, lacking energy reserves, relies on rapid, localized increases in blood flow corresponding to neuronal activity, termed functional hyperemia (FH), for proper function. Notably, impaired FH, correlated with endothelial cell dysfunction, has been reported in the 16p11.2 locus deletion mouse model of autism (16p11.2df/+). Neurovascular coupling (NVC), a synergy between neuronal, vascular, and molecular signaling mechanisms, underlies FH. A fundamental NVC mechanism critically relies on the propagation of a hyperpolarizing signal initiated by capillary endothelial KIR2.1 channels. Hypothesis & Objective: We hypothesized that the NVC impairment in 16p11.2df/+ mice results from dysfunctional KIR2.1 channels. We aimed to assess NVC phenotypes and characterize KIR2.1 channel function and expression in male and female 16p11.2df/+ mice. Method: We utilized the capillary-parenchymal arteriole (CaPA) preparation, an advanced ex vivo pressure myography technique we developed, and immunohistochemistry on male and female 16p11.2df/+ mice and their littermate controls. KIR2.1 function and capillary-arteriole signaling in NVC was assessed by measuring upstream arteriolar dilation in response to capillary stimulation with 10 mM K+. Results: Capillary stimulation with 10mM K+ elicited 35% and 60% attenuation of upstream arteriolar dilation in female and male 16p11.2df/+ mice, respectively, compared to littermate controls. Further, male 16p11.2df/+ mice exhibited 60%, and females 80%, attenuated vasodilatory response to direct arteriolar KIR2.1 stimulation with 10mM K+, indicating impaired channel function. Endothelial cell-specific KIR2.1 stimulation of arterioles was only impaired in males, indicated by an EC50 shift of 0.2µM to 0.75µM in an NS309 dose curve, a KIR2.1 indirect agonist. Immunohistochemistry revealed 2x increased capillary KIR2.1 channel expression in both male and female 16p11.2df/+ mice. Finally, capillary stimulation with 12 and 15mM K+ was sufficient to rescue upstream arteriolar vasodilation to 67% and 100% of control values, respectively, in male 16p11.2df/+ mice. Conclusions: Our results reveal sex differences in cerebral vascular impairment in ASD, potentially contributing to its higher prevalence in males. These data indicate that endothelial KIR2.1 channel function is impaired in 16p11.2df/+ mice, despite a compensatory upregulation of the channel expression. Additionally, NVC signaling is severely reduced and likely contributes to the FH deficits observed in 16p11.2df/+ mice; however, increasing conductance of KIR2.1 channels via increased extracellular K+ appears sufficient to restore this response. Overall, these data suggest that targeting Kir2.1 channel activation may provide a promising therapeutic avenue for individuals with ASD. This research was funded by PR 5T32GM007635-45, NHLBI: FD R01HL136636, NINDS: FD RF1/R01NS129022, R01/RF1NS140137, and the Ludeman Family Center for Women’s Health Research. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.