Experimentally, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain-of-function to CSD generation in FHM3. Those findings are supported by the two-neuron conductance-based model with dynamic ion concentrations we developed.
Model Type: Neuron or other electrically excitable cell; Extracellular
Currents: I Na,p; I K; I Cl, leak; I K,leak; I Na, leak; Na/K pump; I Na,t; NKCC1; KCC2; I_AHP
Genes: Nav1.1 SCN1A
Model Concept(s): Spreading depolarization; Dynamic extracellular concentrations
Simulation Environment: XPPAUT
References:
Chever O et al. (2021). Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels The Journal of clinical investigation. 131 [PubMed]