Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Objective Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated Ca_V2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α_1A subunit of Ca_V2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. Methods We employed in vivo multiphoton microscopy of the genetically encoded Ca²⁺-indicator yellow cameleon to investigate synaptic morphology and [Ca²⁺]_i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the Ca_V2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. Results FHM1 mutations elevate neuronal [Ca²⁺]_i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a Ca_V2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca²⁺]_i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca²⁺]_i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. Interpretation Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca²⁺ homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.