Enhanced Excitatory Transmission at Cortical Synapses as the Basis for Facilitated Spreading Depression in CaV2.1 Knockin Migraine Mice

Abstract

Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(V)2.1 (P/Q-type) Ca(2+) channels. Knockin mice carrying a FHM1 mutation show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 mice. We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses. Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation. The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

“…We observed a lower SD threshold in vivo in S218L mice than in WT and R192Q animals, suggesting that only the S218L Ca V 2.1 channel gain-of-function mutation was sufficiently pathophysiological to promote the initiation of SD as a result of cortical electrical depolarization. This finding was somewhat unexpected because previous data indicated a lowered SD threshold associated with both FHM-1 mutations (8, 9) and also because both R192Q and S218L mice display enhanced glutamatergic activity in cortical neurons (15,16,32). Notably, the use of isoflurane (instead of urethane) in the current study may have differentially affected the SD threshold.…”

“…The gain-of-function alterations of Ca V 2.1 channels containing R192Q or S218L mutations likely underlie the observed increases in SD speed in these strains; this possibility is supported by studies demonstrating enhanced synaptic activity in cortical neurons from both R192Q (15,32) and S218L mice (16).…”

“…FHM-1 mutations introduced into the orthologous Cacna1a gene produce transgenic mice with phenotypes that closely mimic both the milder (R192Q) and more severe (S218L) symptoms described in FHM-1 patients with these mutations (8,9). FHM-1 mutations have been shown to produce an overall gain-of-function increase in calcium conductance at physiological membrane potentials (10,11); given the wellestablished role of the channels in the calcium-mediated release of vesicular neurotransmitters, this increase can explain the increased synaptic activity observed in the mutant animals (12)(13)(14)(15)(16).…”

Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

“…The genetic forms of migraine (familial hemiplegic migraine) are rare diseases, which involve defects in sodium or calcium channels, or in the Na + -K-ATPase (Barrett et al, 2008). The well-established genetic basis of some familial hemiplegic migraine phenotypes has provided a unique opportunity for studies of the cellular migraine mechanisms (Tottene et al, 2009). The cortex of migraineurs is believed to be hyperexcitable due to impaired habituation, which may explain the increased vulnerability to CSD in these patients (Schoenen et al, 2003).…”

Exploitation of the spreading depolarization-induced cytotoxic edema for high-resolution, 3D mapping of its heterogeneous propagation paths

“…However, there is ample evidence that SD also occurs during migraine aura (12), and the toxicity of a single SD wave is not sufficient to induce lasting neuronal damage when it runs in normal, well-nourished tissue. Hence, there is need for the search for triggers more congruent with the hypothesis that SD associated with migraine aura does not usually emerge from injury but from episodic disruptions of the excitation/inhibition balance and hyperactivity of cortical circuits as a result of excessive recurrent excitation (13).…”