Multiple Sclerosis (MS) is a debilitating central nervous system (CNS) disorder that leads to significant motor and cognitive impairments. A hallmark of MS pathology is endoplasmic reticulum (ER) stress, typically counteracted by the Unfolded Protein Response (UPR). The PAC1 receptor, abundantly expressed in oligodendrocytes and neurons, has emerged as a promising therapeutic target due to its potential to mitigate ER stress.

This study investigates the impact of PAC1 deficiency on myelin density, neuronal health, and ER stress during demyelination and remyelination in the cuprizone mouse model of MS.

Real-time qPCR demonstrated a marked downregulation of myelin markers (MOG, MBP, Olig2) in the motor cortex and white matter of PAC1-/- mice relative to PAC1+/+ controls during demyelination (p<0.0001), corroborated by immunofluorescence analysis of myelin markers and diminished myelin density in the corpus callosum, as determined by Luxol Fast Blue staining. This downregulation persisted at both 1 and 3 weeks post-remyelination when compared to PAC1+/+. Additionally, UPR markers (ERN1, ATF4, ATF6, DDIT3) were significantly lower in PAC1-/- mice, reflecting a compromised ability to manage ER stress. Behavioral assessments (Open Field, Rotarod) revealed significant motor deficits in PAC1-/- mice. Maxadilan (PAC1-specific agonist) ameliorated cuprizone-induced motor coordination deficits compared to saline controls in PAC1+/+ mice (p<0.05).

This study identifies a distinct CNS phenotype in PAC1-/- mice during demyelination and after spontaneous remyelination, with impaired myelin health and behavioral deficits likely linked to unresolved ER stress. These findings underscore the PACAP/PAC1 axis as a potential therapeutic target for modulating ER stress in MS.