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
View: Text | PDF
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

×

Figure 6

Higher susceptibility to CSD in heterozygous animals in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Higher susceptibility to CSD in heterozygous animals in vivo. (A) Repres...
(A) Representative recordings of DC potential (top) and ECoG signal (below) of CSD in WT and heterozygous littermates after local application of 300 mM KCl. (B) Box plots represent the frequency of CSD events, elicited as in A, showing a higher CSD frequency in heterozygous animals compared with WT littermates in 2-month-old animals (*P < 0.05) and a trend in 9-month-old animals (P < 0.10) (group sizes: 2 months: wt/wt, n = 17; mut/wt, n = 13; 9 months: wt/wt, n = 18; mut/wt, n = 19; Mann-Whitney rank sum test). (C) CSD frequency in WT and heterozygous male and female animals without differences between sexual phenotype (P = 0.67; group sizes: female: wt/wt, n = 17; mut/wt, n = 13; male: wt/wt, n = 18; mut/wt, n = 19; Mann-Whitney rank sum test). (D) Latency (s) of the first CSD after stimulation. Heterozygous littermates showed a shorter latency (*P < 0.05; group size: wt/wt, n = 16; mut/wt, n = 13; Mann-Whitney rank sum test). (E) CSD propagation velocity (mm/min) was similar in both genotypes (P = 0.488; group size: wt/wt, n = 12; mut/wt, n = 13; Mann-Whitney rank sum test). (F) CSD threshold determined by electrical stimulation. Five of 6 heterozygous animals (83%) showed a CSD at the given thresholds, whereas these stimulation intensities were not able to elicit any CSDs in WT littermates (median: 20 μC; group size: wt/wt, n = 6; mut/wt, n = 6).