Ian's synopsis on: "Glutamate signaling and plume characteristics in a genetic mouse model of migraine with aura" by Parker et al.

Migraine is a neurological disorder that commonly consists of symptoms such as extreme headaches and sensory amplifications. It is commonly associated with aura, which is characterized by spreading sensory hallucinations (flashing visual perceptions, numbness, and tingling). Spreading depolarization (SD) is known to be the underlying cause of migraine aura. Familial hemiplegic migraine type 2 (FHM2) is a form of migraine with aura that arises from loss-of-function mutations to the gene ATP1A2 (the gene encoding the predominantly astrocytic alpha2 Na+/K+-ATPase). Astrocytes in heterozygous FHM2 mice show slower uptake kinetics of glutamate due to a 50% reduction in the concentration of glutamate transporter GLT-1a in perisynaptic astrocyte processes. This serves as an effective mouse model for migraine with aura. How this astrocytic mutation reshapes glutamate signaling in awake FHM2 mice is largely unknown. Here, they use the fluorescent glutamate reporter iGluSnFR to measure glutamate in FHM2 and WT mice. They found that FHM2 mice exhibited spontaneous glutamatergic “plumes” that were generally circular in nature and appeared to spread from a central origin. Plumes occurred predominantly in superficial cortical layer 1 (L1a), and much less frequently in deeper L1b and L2/3. This correlated with the density of GLT1a+ astrocyte processes, as L1a exhibited a reduced density of these processes as compared to L2/3, and superfusion of the glutamate transporter inhibitor TFB-TBOA caused a large number of plumes in L1a, leading the researchers to believe that plumes are a result of impaired glutamate uptake. Glutamate release during plumes is likely due to Ca2+-mediated vesicular release from neurons. Once glutamate is released, the presence of plumes is gated by impaired or inefficient glutamate clearance by astrocytes. Plumes tend to occur during the depolarization phase, following the glutamatergic wavefront commonly seen in SD and rises in glutamate and plume frequency predict the onset of SD. This links plumes to the key translational phenotype of FHM2 and all other models of migraine with aura.

Ian

Reference 

Parker, P. D., Suryavanshi, P., Melone, M., Reinhart, K. M., Sawant-Pokam, P. A., Kaufmann, D., Theriot, J. J., Pugliese, A., Conti, F., Shuttleworth, C. W., Pietrobon, D., Brennan, K. C. (2020). Non-canonical glutamate signaling in a genetic model of migraine with aura. NEURON, 109(4), 561-740. doi:10.1101/2020.01.02.891770