<p>Migraine is a prevalent primary headache disorder that significantly impairs daily life. Recent imaging studies have suggested that chronic migraine may be associated with changes in the function of the glymphatic system. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na⁺/K⁺-ATPases. We used cerebrospinal fluid (CSF) fluorescence tracing to demonstrate that impairment of the inflow and outflow functions of the glymphatic system was observed in FHM2 mice. Using two-photon recording, we observed exaggerated neurovascular coupling in the barrel cortex of FHM2 mice. This abnormal neurovascular coupling resulted in a decrease in AQP4 expression within the perivascular astrocyte endfoot. This alteration may be a significant mechanism contributing to impairment of the glymphatic system in FHM2 mice. In vitro, primary astrocyte cultures were established and it was found that astrocytes derived from FHM2 exhibited impaired K⁺ transport function, which may be associated with exaggerated neurovascular coupling. Overall, our study reveals that the glymphatic system is significantly impaired in FHM2 mice, with abnormal neurovascular coupling playing a key role in decreased AQP4 expression in astrocytes, this providing a new ways of approaching to migraine pathophysiology.</p> Graphical abstract <p></p>