Astroglial Kir4.1 and AQP4 Channels: Key Regulators of Potassium Homeostasis and Their Implications in Autism...

Astroglial Kir4.1 and AQP4 channels are pivotal regulators of potassium (K⁺) and water homeostasis in the brain, playing essential roles in maintaining neuronal stability, facilitating synaptic transmission, and supporting overall brain function. Kir4.1 channels promote the efficient uptake of K⁺ ions from the extracellular space, particularly during periods of high neuronal activity, thereby preventing excessive neuronal excitability-a condition linked to several neurological disorders, including Autism Spectrum Disorder (ASD). Meanwhile, AQP4 channels, predominantly expressed in the astrocytic end-feet at the blood-brain barrier, regulate water transport across cell membranes, ensuring osmotic balance that complements the function of Kir4.1 in K⁺ clearance. Recent studies have underscored the critical link between dysfunctions in these channels and the pathophysiology of ASD, a complex neurodevelopmental disorder characterized by a broad range of social, communicative, and behavioral impairments. Mutations or dysregulations in Kir4.1 and AQP4 channels can disrupt K⁺ and water homeostasis, exacerbating neuronal hyperexcitability and contributing to hallmark ASD symptoms, such as sensory processing abnormalities, social deficits, and an increased risk of seizures. This review synthesizes current findings, focusing on the molecular mechanisms of Kir4.1 and AQP4 channels, their role in astrocyte-neuron interactions, and their pathophysiological implications in ASD. It also provides a detailed discussion of potential therapeutic interventions targeting these channels to mitigate ASD symptoms.