Exploring the potential pathogenesis of migraine using glutamatergic neuron models derived from induced pluripotent stem cells (iPSCs) of migraine patients.

Abstract

Migraine is a complex neurological disorder influenced by multiple genetic susceptibility factors, yet current animal models fail to fully recapitulate its human-specific pathophysiology. In this study, we explored the potential mechanisms underlying migraine by examining functional abnormalities and molecular dysregulation in glutamatergic neurons derived from induced pluripotent stem cells (iPSCs) of migraine patients. As key excitatory cells in the central nervous system, glutamatergic neurons are implicated in migraine through altered excitability, ion channel dysfunction, and dysregulation of nociceptive signaling molecules. iPSCs from both migraine patients and healthy controls were differentiated into glutamatergic neurons. Electrophysiological properties and sodium and potassium channel functions were assessed using whole-cell patch-clamp recordings. Expression levels of migraine-associated molecules, including P2RX3, calcitonin gene-related peptide (CGRP), and c-Fos, were evaluated via immunofluorescence and quantitative real-time PCR. Dysfunction of glutamatergic neurons, involving ion channel dysregulation and abnormal molecular expression, may be implicated in migraine pathology and may provide potential targets for therapeutic intervention. The iPSC-based model may help to address some limitations of animal studies and offers a potential platform for migraine precision medicine research. As a proof-of-principle study, these findings highlight the feasibility of using iPSC-derived glutamatergic neurons to explore migraine mechanisms. While preliminary, this model may serve as a valuable foundation for future translational and precision medicine research.