ArticleThe Journal of clinical investigation2021
Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.Pflugers Archiv : European journal of physiology · 2024Pooled it
- Hemiplegic migraine: genetics and pathophysiology.The Journal of clinical investigation · 2026Review
- Review
- Elicited Repetitive Daily Blindness Associated With Gain-of-FunctionNeurology. Genetics · 2026Article
- From bench to bedside: relevant animal models across the migraine attack phases.The journal of headache and pain · 2026Review
- Tsunamis hiding in plain sight: spreading depression in clinical neurology.Nature reviews. Neurology · 2026Review
- Headache associated with adverse cognitive trajectories in Chinese aging cohort: a group-based trajectory modeling study.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- Unraveling the Cross-Tissue Neuroimmune-Vascular Genetic Architecture of Migraine Using Integrated Multi-Omics, Single-Cell, and Spatial Transcriptomics: Prioritizing T-Cell Regulatory Networks and Peripheral Targets.International journal of molecular sciences · 2026Article
- Mechanisms underlying the increased susceptibility to initiation of cortical spreading depression in a genetic mouse model of migraine.The journal of headache and pain · 2025Article
- Article
- The mysterious link between migraine aura and migraine headache.PLoS biology · 2025Article
- Axon initial segment structure and function in health and disease.Physiological reviews · 2025Review
- Dynamics and conditions for inhibitory synaptic current to induce bursting and spreading depolarization in pyramidal neurons.Scientific reports · 2025Article
- Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine.The journal of headache and pain · 2025Review
- Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.CNS & neurological disorders drug targets · 2025Review
- Energy metabolism disorders in migraine: triggers, pathways, and therapeutic repurposing.Frontiers in neurology · 2025Review
- Hallmarks of primary headache: part 1 - migraine.The journal of headache and pain · 2024Review
- The Role of Astrocytes in Migraine with Cortical Spreading Depression: Protagonists or Bystanders? A Narrative Review.Pain and therapy · 2024Review
- Article
- Probing intracellular potassium dynamics in neurons with the genetically encoded sensor lc-LysM GEPII 1.0 in vitro and in vivo.Scientific reports · 2024Article
Corrections and comments
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.