Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation

Jayasankar Kosaraju, Matthew Seegobin, Ayden Gouveia, Charvi Syal, Sailendra Nath Sarma, Kevin Jiaqi Lu, Julius Ilin, Ling He, Fredric E. Wondisford, Diane Lagace, Yves De Repentigny, Rashmi Kothary, Jing Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.

Original languageEnglish (US)
Article number113454
JournalExperimental Neurology
Volume334
DOIs
StatePublished - Dec 2020

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

Keywords

  • CBP S436 phosphorylation
  • Differentiation
  • Mature oligodendrocytes
  • Metformin
  • Myelin
  • Oligodendrocyte precursors
  • Social interaction
  • White matter demyelinating disease

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