# Selective vulnerability of GABAergic neurons in chronic migraine

## TL;DR

This study finds that GABAergic neurons are selectively vulnerable in male mice with chronic migraine, suggesting sex-specific differences in migraine mechanisms.

## Contribution

The study identifies a male-specific vulnerability of GABAergic neurons in chronic migraine and highlights sex-dependent pathophysiological differences.

## Key findings

- Male, but not female, NTG-treated mice showed a selective reduction in GABAergic neurons in key brain regions.
- Male chronic migraine mice exhibited elevated ΔFosB, caspase-3, and stress-related neuropeptides like PACAP and BDNF.
- Downregulation of GABA signaling and overexpression of NKCC1 were observed in the choroid plexus of male mice.

## Abstract

Migraine is the second leading cause of neurological disability and has a strong genetic component. Previous linkage studies have identified a candidate migraine susceptibility locus on chromosome Xq24-28, which harbors several GABAA receptor subunit genes. Despite its inhibitory role in the central nervous system, the contribution of the GABAergic system to migraine pathophysiology remains insufficiently understood. This study elucidates the role of GABAergic neurons in chronic migraine using established rodent models. We induced basal hypersensitivity as a preclinical model of chronic migraine by administering repeated intraperitoneal injections of nitroglycerin, a well-established migraine trigger, every other day over a nine-day period. Mechanical hypersensitivity, a hallmark of migraine-associated allodynia, was assessed using von Frey filaments, before and after NTG treatment. NTG-treated animals exhibited a progressive increase in mechanical sensitivity compared to controls, consistent with the development of a chronic migraine-like state.

Notably, a selective reduction in GABAergic neurons was observed in male, but not female, NTG-treated mice, specifically within key brain regions associated with pain processing and psychiatric circuits, from the locus coeruleus in the brainstem through the basal forebrain (notably the amygdala) to the neocortex and hippocampus. This loss of GABAergic neurons was accompanied by elevated expression of ΔFosB, a marker of sustained neuronal activation, and increased apoptotic signaling indicated by active caspase-3 staining. Furthermore, male chronic migraine mice showed upregulation of stress-related neuropeptides, including PACAP and its receptor PAC1, as well as downstream effectors BDNF and TRK1B. Gene expression analysis revealed downregulation of GABA signaling components in the choroid plexus of the fourth ventricle, including aberrant overexpression of the chloride cotransporter NKCC1.

These findings reveal a male-specific vulnerability of GABAergic neurons in chronic migraine and suggest a sex-dependent divergence in the underlying pathophysiological mechanisms. This highlights the critical need for sex-specific approaches to migraine research and therapeutic development.

The online version contains supplementary material available at 10.1186/s10194-025-02223-9.