Martin Krupa
Martin Krupa

Modeling cortical spreading depression induced by the hyperactivity of interneurons

Martin Krupa
krupa@unice.fr
Université Côte d'Azur-Inria
Cortical spreading depression (CSD) is a wave of transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. It is a proposed pathological mechanism of migraine with aura. Some molecular/cellular mechanisms of migraine with aura and of CSD have been identified studying a rare genetic form: familial hemiplegic migraine (FHM). FHM type 1 & 2 are caused by mutations of the CaV 2.1 Ca2+ channel and the glial Na+/K+ pump, respectively, leading to facilitation of CSD in mouse models mainly because of increased glutamatergic transmission/extracellular glutamate build-up. FHM type 3 mutations of the SCN1A gene, coding for the voltage gated sodium channel NaV 1.1, cause gain of function of the channel and hyperexcitability of GABAergic interneurons. This leads to the counterintuitive hypothesis that intense firing of interneurons can cause CSD ignition. To test this hypothesis in silico, we developed a computational model of an E-I pair (a pyramidal cell and an interneuron), in which the coupling between the cells in not just synaptic, but takes into account also the effects of the accumulation of extracellular potassium caused by the activity of the neurons and of the synapses. In the context of this model, we show that the intense firing of the interneuron can lead to CSD. We have investigated the effect of various biophysical parameters on the transition to CSD, including the levels of glutamate or GABA, frequency of the interneuron firing and the efficacy of the KCC2 co-transporter. The key element for CSD ignition in our model was the frequency of interneuron firing and the related accumulation of extracellular potassium, which induced a depolarizing block of the pyramidal cell. This constitutes a new mechanism of CSD ignition.
Massimo Mantegazza
Massimo Mantegazza

Waves of cerebral cortex depolarization: focus on a novel mechanism of migraine-linked cortical spreading depression induced by hyperactivation of GABAergic neurons.

Massimo Mantegazza
mantegazza@ipmc.cnrs.fr
Université Côte d'Azur, CNRS UMR7275 IPMC, 660 Route des Lucioles, 06560 Valbonne, FranceIPMC

Spreading depolarization (SD) refers to waves of abrupt, sustained mass depolarization in the gray matter of the central nervous system, observed in different pathological conditions. Cortical spreading depression (CSD) is a SD generated in well-nourished and oxygenated tissue, and characterized by transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. CSD is a proposed pathological mechanism of migraine. Some molecular/cellular mechanisms of migraine with aura and of CSD have been identified studying a rare genetic form: familial hemiplegic migraine (FHM). FHM type 3 is caused by mutations of the SCN1A gene, leading to gain of function of NaV1.1 sodium channels, which are essential for GABAergic neurons’ excitability. I will present our recent results about mechanisms of induction of CSD caused by gain of function of Nav1.1. Acute activation of Nav1.1 with a selective toxin in brain slices, mimicking the effect of FHM3 mutations, induce SD selectively in the cerebral cortex. We tested the role of GABAergic neurons by activating them with optogenetic techniques. Hyperactivity of interneurons is sufficient to ignite CSD by spiking-induced extracellular K+ build-up in the cerebral cortex, but not in other brain structures. GABAergic and glutamatergic synaptic transmission was not required for CSD initiation, but glutamatergic transmission was implicated in CSD propagation in the cortex. These results reveal the key role of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which can be relevant for FHM3 and possibly also for other types of migraine.