Abnormal synaptic <scp>C</scp>a²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

<jats:sec><jats:title>Objective</jats:title><jats:p>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<jats:sub>V</jats:sub>2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α<jats:sub>1A</jats:sub> subunit of Ca<jats:sub>V</jats:sub>2.1 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We employed in vivo multiphoton microscopy of the genetically encoded Ca<jats:sup>2+</jats:sup>‐indicator yellow cameleon to investigate synaptic morphology and [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> 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<jats:sub>V</jats:sub>2.1 gating modifier <jats:italic>tert‐</jats:italic>butyl dihydroquinone on CSD in vivo.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>FHM1 mutations elevate neuronal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a Ca<jats:sub>V</jats:sub>2.1 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 [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium‐overloaded neurons was increased. Neuronal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> surge during CSD was faster and larger, and post‐CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca<jats:sup>2+</jats:sup> homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. Ann Neurol 2015;78:193–210</jats:p></jats:sec>