Selective vulnerability of GABAergic neurons in chronic migraine

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 GABA_A 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.