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Astrocytic Glutamate Transporters and Migraine

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Abstract

Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.

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Notes

  1. * EAAC1, GLT1, GLAST, EAAT4-5 refer to proteins in rodents; EAAT1-5 to proteins in humans; Slc1a1, Slc1a2, Slc1a3, Slc1a6, Slc1a7 to genes in rodents; and SLC1A1, SLC1A2, SLC1A3, SLC1A6, SLC1A7 to genes in humans.

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Acknowledgements

We are indebted to our present and past collaborators who contributed much to the studies on glutamate transporters and migraine reported here. We acknowledge the funding organizations cited in the original papers for their invaluable support.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript, and that they have no financial interests.

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Authors and Affiliations

  1. Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy

    Fiorenzo Conti

  2. Center for Neurobiology of Aging, IRCCS INRCA, Ancona, Italy

    Fiorenzo Conti

  3. Department of Biomedical Sciences and Padova Neuroscience Center (PNC), University of Padova, 35131, Padua, Italy

    Daniela Pietrobon

  4. CNR Institute of Neuroscience, 35131, Padua, Italy

    Daniela Pietrobon

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Both authors contributed to the study conception and design. The first draft of the manuscript was written by FC and DP and both authors commented on previous versions of the manuscript, read and approved the final manuscript.

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Conti, F., Pietrobon, D. Astrocytic Glutamate Transporters and Migraine. Neurochem Res 48, 1167–1179 (2023). https://doi.org/10.1007/s11064-022-03849-w

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