title: Stress hormone corticosterone enhances susceptibility to cortical spreading depression in familial hemiplegic migraine type 1 mutant mice.
abstract: Stress is a putative migraine trigger, but the pathogenic mechanisms involved are unknown. Stress and stress hormones increase neuronal excitability by enhancing glutamatergic neurotransmission, but inhibitory effects have also been reported. We hypothesise that an acute rise in stress hormones, such as corticosteroids which are released after stress, increase neuronal excitability and thereby may increase susceptibility to cortical spreading depression (CSD), the mechanism underlying the migraine aura. Here we investigated effects of acute restraint stress and of the stress hormone corticosterone on CSD susceptibility as surrogate migraine marker, in a transgenic mouse model of familial hemiplegic migraine type 1 (FHM1), which displays increased glutamatergic cortical neurotransmission and increased propensity for CSD. We found that 20-min and 3-h restraint stress did not influence CSD susceptibility in mutant or wild-type mice, despite elevated levels of plasma corticosterone. By contrast, subcutaneous administration of 20mg/kg corticosterone increased CSD frequency exclusively in mutant mice, while corticosterone plasma levels were similarly elevated in mutants and wild types. The effect of corticosterone on CSD frequency was normalised by pre-administration of the glucocorticoid receptor (GR) antagonist mifepristone. These findings suggest that corticosteroid-induced GR activation can enhance susceptibility to CSD in genetically susceptible individuals, and may predispose to attacks of migraine. Although corticosterone levels rise also during acute stress, the latter likely triggers a spatiotemporally more complex biological response with multiple positive and negative modulators which may not be adequately modeled by exogenous administration of corticosterone alone.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Reinald
authors.initials: R
authors.lastname: Shyti
authors.affiliation: Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, MA General Hospital, Harvard Medical School, Charlestown, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sandra H
authors.initials: SH
authors.lastname: van Heiningen
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, MA General Hospital, Harvard Medical School, Charlestown, USA; Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, MA General Hospital, Harvard Medical School, Charlestown, USA.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.affiliation: Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Joëls
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: E.A.Tolner@lumc.nl.
authors.forename: Else A
authors.initials: EA
authors.lastname: Tolner
mesh_terms: D000818:Animals; D013181:Cortical Spreading Depression / Q000502:physiology*; D003345:Corticosterone / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000209:etiology / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; D003345:Corticosterone
keywords: Ca(V)2.1 calcium channels; Cortical spreading depression; Corticosterone; Familial hemiplegic migraine; Glutamate; Migraine; Neuronal hyperexcitability; Stress