# Mechanisms underlying the increased susceptibility to initiation of cortical spreading depression in a genetic mouse model of migraine

## TL;DR

This study explores why a genetic mouse model of migraine is more prone to a brain activity pattern linked to migraine auras.

## Contribution

The study reveals that a specific mutation in calcium channels lowers the threshold for triggering a migraine-related brain activity pattern.

## Key findings

- FHM1 mice reach the threshold for CSD initiation with lower intensity and faster than wild-type mice.
- NMDARs are crucial for CSD initiation, but can be bypassed with strong stimuli in FHM1 mice.
- NMDAR-independent CSDs in FHM1 mice propagate more slowly due to delayed threshold reaching and slower depolarization.

## Abstract

There is evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of CSD initiation in the brain of migraineurs remain unknown. Insights into this question can be obtained by studying the mechanisms underlying the facilitation of CSD initiation in genetic mouse models of migraine. Here, we investigated these mechanisms in knock-in mice carrying a mutation in the CaV2.1 calcium channel, which causes pure familial hemiplegic migraine type 1 (FHM1 mice).

Brief high-KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded in cortical slices from FHM1 mice. This was done before and after application of MK-801. After blocking the glutamate NMDA receptors (NMDARs), stimuli up to 21 times the control CSD threshold were applied.

A delayed activation of NMDARs above a critical threshold level is necessary for CSD initiation in FHM1 mice. This threshold level of NMDAR activation is quantitatively similar in FHM1 and WT mice, but is reached with a stimulus of much lower intensity and more rapidly in FHM1 mice, thus accounting for the facilitation of CSD initiation in these migraine mouse models. While, no matter the intensity of stimulation, CaV channels are necessary for CSD initiation, the necessity of NMDARs can be overcome by largely suprathreshold stimuli in FHM1 mice; however, these NMDAR-independent CSDs propagate much more slowly than the control CSDs, due to both a longer time needed to reach the threshold for CSD initiation after the beginning of the prodromal neuronal depolarization and a slower regenerative CSD depolarization.

FHM1 mice are more susceptible to CSD initiation than WT mice because the critical threshold level of NMDAR activation, necessary for CSD initiation in both genotypes, is attained with stimuli of much lower intensity and more rapidly in FHM1 mice. Our findings give insights into potential mechanisms of CSD initiation in migraine.