Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model
Eva Auffenberg, Ulrike B.S. Hedrich, Raffaella Barbieri, Daniela Miely, Bernhard Groschup, Thomas V. Wuttke, Niklas Vogel, Philipp Lührs, Ilaria Zanardi, Sara Bertelli, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Michael Pusch, Martin Dichgans, Holger Lerche, Paola Gavazzo, Nikolaus Plesnila, Tobias Freilinger
Eva Auffenberg, Ulrike B.S. Hedrich, Raffaella Barbieri, Daniela Miely, Bernhard Groschup, Thomas V. Wuttke, Niklas Vogel, Philipp Lührs, Ilaria Zanardi, Sara Bertelli, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Michael Pusch, Martin Dichgans, Holger Lerche, Paola Gavazzo, Nikolaus Plesnila, Tobias Freilinger
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Research Article Neuroscience

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

Abstract

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

Authors

Eva Auffenberg, Ulrike B.S. Hedrich, Raffaella Barbieri, Daniela Miely, Bernhard Groschup, Thomas V. Wuttke, Niklas Vogel, Philipp Lührs, Ilaria Zanardi, Sara Bertelli, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Michael Pusch, Martin Dichgans, Holger Lerche, Paola Gavazzo, Nikolaus Plesnila, Tobias Freilinger

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Figure 3

Slowed inactivation of Na+ currents in acutely isolated cerebellar Purkinje cells of mutant mice.

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Slowed inactivation of Na+ currents in acutely isolated cerebellar Purki...
(A) Image of an acutely dissociated cerebellar Purkinje neuron (marked by an arrow) and a patch pipette. Scale bar: 100 μm. (B) Representative traces of Na+ currents recorded from dissociated neurons of wt/wt, mut/wt, and mut/mut animals were elicited by voltage steps from –70 to 5 mV in 5 mV increments (duration 15 ms, holding potential –90 mV). (C) Box plots of the peak current density of neurons recorded from animals with the indicated phenotypes (*P < 0.05, ANOVA on ranks with Dunn’s post hoc test, wt/wt: n = 27; mut/wt: n = 33, mut/mut: n = 12). (D) Box plots of the voltage of half-maximal inactivation for the indicated phenotypes. V1/2 was significantly shifted to more depolarized potentials in neurons of mut/mut animals in comparison to wt/wt and mut/wt (wt/wt: n = 27; mut/wt: n = 33, mut/mut: n = 12, *P < 0.05 ANOVA on ranks with Dunn’s post hoc test). (E) Dot plots of fast (left) and slow (right) time constants of fast inactivation, respectively, plotted over different voltage steps. Data are shown as mean ± SEM (wt/wt: n ≤ 14; mut/wt: n ≤ 31, mut/mut: n ≤ 13, *P < 0.05 2-way ANOVA with Tukey test for pairwise multiple comparison). (F) Box plots of remaining current at the end of a 15 ms test pulse to –25 mV (I15ms) divided by the peak current (IPeak) recorded at the same voltage. The remaining current was significantly increased in neurons of mut/mut animals in comparison to wt/wt and mut/wt (wt/wt: n = 20; mut/wt: n = 25, mut/mut: n = 9, *P < 0.05 ANOVA on ranks with Dunn’s post hoc test).