Background: It has been suggested from clinical studies that migraine is associated with changes in neurovascular coupling (NVC) although the underlying mechanism is unclear. We addressed this question by studying heterozygous mice bearing a mutation (G301R) of the α2 isoform Na+,K+-ATPase, which is known to be associated with familial hemiplegic migraine type 2 (FHM2) in humans. We have previously shown that this mutation leads to increased contractility of cerebral arteries associated with increased Src-kinase dependent Ca2+-sensitivity in vascular smooth muscle cells. Moreover, we found that pre-constricted cerebral arteries from FHM2 mice dilated stronger to increased K+ concentrations (8 – 12 mM) than arteries from wild types. This suggests stronger vasodilation to elevation of interstitial K+ in vivo, i.e. NVC, in FHM2 mice. Methods: NVC was assessed using confocal microscopy in brain slices loaded with CalciumGreen/AM. Parenchymal arteriole diameter and [Ca2+]i changes in astrocytes and smooth muscles were measured ex-vivoin response to neuronal excitation induced by electric field stimulation. Change in cerebral blood flow in response to whisker stimulation was measured noninvasively using Laser Speckle Imaging. Results: Neuronal excitation ex vivo led to Ca2+ waves in astrocytic endfeet and relaxation of adjacent arterioles. Arterioles from FHM2 mice increased the diameter more than arterioles from wild type mice (7.83 ± 0.87%, n=8 vs. 4.03±0.39%, n=7; P=0.001). The decrease in smooth muscle [Ca2+]i associated with this relaxation was the same in both groups but [Ca2+]i recovery in astrocytes was significantly slower in FHM2 brains. Whiskers stimulation increased blood flow in the corresponding part of the sensory cortex and this response was significantly stronger in FHM2 mice. Conclusion: In vivo and ex vivo experiments suggested NVC disturbances in a mouse model for FHM2. Cerebral arterioles from FHM2 mice showed increased dilations to excitation of nearby neurons even though the changes in smooth muscle [Ca2+]i was similar to that in wild types. We suggest that increased dilation of cerebral arterioles from FHM2 mice consequent to neuronal activity is due to altered Ca2+-sensitivity of smooth muscle cells, likely caused by increased Src-kinase activity.