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Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model
Eva Auffenberg, … , Nikolaus Plesnila, Tobias Freilinger
Eva Auffenberg, … , Nikolaus Plesnila, Tobias Freilinger
Published September 21, 2021
Citation Information: J Clin Invest. 2021;131(21):e142202. https://doi.org/10.1172/JCI142202.
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Research Article Neuroscience

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

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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 7

Increased extracellular [K+]e during CSD in slices of heterozygous versus WT animals.

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Increased extracellular [K+]e during CSD in slices of heterozygous versu...
(A) IOS of CSD induced by local KCl application (Puff) in slice of wt/wt animal with K+ sensitive and LFP electrodes. Scale bar: 500 μm. (B) Traces of K+ sensitive recording (top) and LFP signal (bottom) during CSD for slices of wt/wt (left) and mut/wt animals (right). CSD-recording elicited by KCl-application (arrow) (left). Averaged [K+]e dynamics before and during CSD (wt/wt: 21 slices; mut/wt: 30 slices) (right). Magnified boxes indicate AUC from point at which K+ signal left baseline (threshold: +0.1 mM) to inflection-point of [K+]e curve (see Supplemental Figure 5B). (C) Success rate of CSD induction in slices of both genotypes (wt/wt: n = 43 slices from 12 animals [43/12]; mut/wt: 41/11; P < 0.001; Fisher’s exact test). CSD failed category includes CSDs that aborted before reaching K+ and DC electrodes. (D) Propagation velocity was increased in mut/wt compared with wt/wt animals (wt/wt: 22/10; mut/wt: 31/11; ***P < 0.001; Mann-Whitney rank sum test). (E) [K+]e at inflection point of K+ signal (determined as in Supplemental Figure 5B) and maximum [K+]e (right) during CSD. [K+]e was increased in slices of heterozygous compared with WT animals (wt/wt: 22/10; mut/wt: 31/11; **P < 0.01, ***P < 0.001; Mann-Whitney rank sum test). (F) [K+]e increased earlier in slices of heterozygous compared with WT animals. Time at which [K+]e started to increase to inflection point of K+ signal (left) and from inflection point to maximum peak (right). Initial rise of [K+]e started earlier in mut/wt compared with wt/wt animals (wt/wt: 22/10; mut/wt: 31/11; *P < 0.05; Mann-Whitney rank sum test). Time from inflection point to peak concentration was not different between genotypes (wt/wt: 22/10; mut/wt: 31/11; Mann-Whitney rank sum test). (G) AUC from start of [K+]e increase to inflection point of K+ signal (as shown in B) increased in slices of mut/wt compared with wt/wt animals (wt/wt: 22/10; mut/wt: 31/11; **P < 0.01; Mann-Whitney rank sum test).

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