Depression mechanism.
Oana Chever1,2,#, *, Sarah Zerimech1,2,#, Alexandre Loucif1,2, Marion Ayrault1,2, Fabrice Duprat1,2, Sandrine Cestèle1,2 and Massimo Mantegazza1,2,*
1 Université Côte d’Azur, Valbonne-Sophia Antipolis, France.
2 CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Valbonne-Sophia Antipolis, France.
Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR 7275 and Université Côte d’Azur, 660 Route des Lucioles, 06560 Valbonne-Sophia Antipolis, France. Tel. +33 (0)493953425 FAX +33 (0)493957708
Short title: GABAergic neurons hyperactivity in CSD.
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AbstractCortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene) cause Familial Hemiplegic Migraine type-3 (FHM 3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture.
However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that hyperactivity of cortical interneurons or NaV1.1 gain-of-function is sufficient to ignite CSD by spiking-induced extracellular K+ build-up.
GABAergic and glutamatergic synaptic transmission was not required for CSD initiation, but glutamatergic transmission was implicated in CSD propagation in the cortex. Our results reveal the key role of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, relevant for FHM3 and possibly also for other types of migraine.
Keywords: FHM, aura, SCN1A,
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IntroductionThe proposed mechanism of migraine with aura (MA) is cortical spreading depression (CSD), a wave of transient intense network hyperexcitability leading to a long lasting depolarization block of neuronal firing. CSD initiates focally and then slowly propagates in the cerebral cortex, causing migraine aura and possibly inducing headache by sensitization of meningeal nociceptors (Ferrari, Klever et al., 2015, Pietrobon &
Moskowitz, 2014). CSD events have been observed and extensively studied for decades, but specific pathological mechanisms that lead to CSD initiation are still far from being completely understood and sorted out. A mendelian form of MA characterized by hemiparesis during the attacks, Familial Hemiplegic Migraine (FHM), has allowed the identification of some molecular/cellular pathological mechanisms (Ferrari et al., 2015, Pietrobon & Moskowitz, 2014), and has become a model disease for more common forms and for studies of mechanisms of CSD. FHM type 1 (FHM1) is caused by gain of function mutations of the α1 subunit of the CaV2.1 P/Q type Ca2+ channel (the CACNA1A gene) (Ophoff, Terwindt et al., 1996), FHM type 2 (FHM2) by loss-of-function mutations of the α2 subunit of the glial Na+/K+ pump (the ATP1A2 gene) (De Fusco, Marconi et al., 2003).
Increased susceptibility to experimentally ignited CSD has been reported in FHM1 and FHM2 genetic mouse models (Leo, Gherardini et al., 2011, van den Maagdenberg, Pietrobon et al., 2004), which is caused by increased network excitability induced by excessive release or insufficient reuptake of glutamate (Capuani, Melone et al., 2016, Tottene, Conti et al., 2009, Vecchia, Tottene et al., 2014), consistent with a similar overall mechanism. FHM3 is caused by mutations of NaV1.1 (SCN1A) Na+ channel (Dichgans, Freilinger et al., 2005), which is particularly important for GABAergic neurons’
excitability (Yu, Mantegazza et al., 2006). Numerous epileptogenic NaV1.1 mutations have been identified; they cause loss-of-function of the channel leading to decreased excitability of GABAergic neurons, reduced inhibition and consequent hyperexcitability of cortical networks (Catterall, Kalume et al., 2010, Guerrini, Marini et al., 2014, Hedrich,
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Liautard et al., 2014, Ogiwara, Miyamoto et al., 2007, Yu et al., 2006). We and others have provided evidence that, in contrast to epileptogenic mutations, FHM3 mutations cause instead gain-of-function of the channel and hyperexcitability of transfected GABAergic neurons in primary culture (Cestele, Labate et al., 2013a, Cestele, Scalmani et al., 2008, Cestele, Schiavon et al., 2013b, Fan, Wolking et al., 2016, Mantegazza &Cestele, 2017). Thus, these results point to different, novel and counterintuitive mechanisms in comparison to FHM1 and FHM2 mutations. However, there is not yet a causal link between NaV1.1 gain-of-function/GABAergic neurons’ hyperactivity and CSD, and it is not clear whether and how CSD could be generated by these dysfunctions. In particular, this would be a novel pathological role for GABAergic neurons, which have never been implicated before in CSD generation. Here, we addressed these issues inducing acute NaV1.1 gain-of-function and performing selective optogenetic stimulation of GABAergic neurons, carrying out experiments in vivo, ex vivo in brain slices and in vitro in cell lines.