Pde4 mediates MHCII expression in oligodendroglia
Abstract
Chronic psychosocial stress is a major precipitant of Major Depressive Disorder (MDD), yet the glial mechanisms that translate sustained stress into maladaptive myelin and immune changes remain unclear. Using chronic social defeat stress and single-nucleus RNA sequencing of anterior medial PFC (mPFC) oligodendroglia, we identified a mature-oligodendrocyte cluster almost exclusively from stress-susceptible animals, marked by immune genes (MHCII) and upregulated Pde4b. Integration with a human MDD single-nucleus RNA sequencing dataset confirmed a conserved immune-like oligodendrocyte (ImOL) subset coexpressing Plp1 and Cd74 and enriched for Pde4b. Mechanistically, PDE4 inhibition with crisaborole elevated cAMP–PKA–CREB signaling, blocked IFNγ-induced MHCII expression, and engaged the eIF2α–ATF4/CHOP arm of the integrated stress response (ISR). In vivo modulation of the ISR with ISRIB or guanabenz bidirectionally controlled ImOL prevalence and stress-related behaviors. These findings position Pde4b–cAMP–ISR signaling as a regulator of oligodendroglial immune phenotypes and a promising target to modulate myelination and neuroinflammation in stress-related disorders.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Miguel M. Madeira
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Zachary Hage
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Dimitris Koliatsis
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Alexandros G. Kokkosis
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Kimberly Nnah
Scholars in Biomedical Sciences Program, Renaissance School of Medicine at Stony Brook University
Alexander J. Rhee
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Gilbert J. Rahme
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University
Katherine Kamvisios
Department of Pharmacological Sciences, Renaissance School of Medicine at Stony Brook University
Antonis E. Koromilas
Barbara Rosati
Department of Physiology and Biophysics Renaissance School of Medicine at Stony Brook University
David McKinnon
Program in Neuroscience, Stony Brook University
Stella E. Tsirka
Molecular and Cellular Pharmacology Graduate Program, Renaissance School of Medicine at Stony Brook University