Oligodendrocyte lineage cell-specific GPR17/Gelsolin signaling regulates remyelination and cognitive recovery after subarachnoid hemorrhage

  • Exp Neurol. 2026 Sep:403:115819. doi: 10.1016/j.expneurol.2026.115819.
Song Tan  1 ,  Yingwen Wang  2 ,  Xuesong Li  1 ,  Yajun Zhu  1 ,  Zichao Huang  1 ,  Chunyue Deng  3 ,  Rui Tang  4 ,  Jianjun Zhong  5 ,  Zongduo Guo  6
Affiliations
  • 1. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Clinical College, Chongqing university, Chongqing, China.
  • 3. Department of Pharmacy, Chongqing university Cancer hospital, Chongqing, China.
  • 4. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 5. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 6. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 42107622 DOI: 10.1016/j.expneurol.2026.115819
Abstract

Aims: Cognitive impairment following subarachnoid hemorrhage (SAH) is strongly associated with myelin sheath damage. G protein-coupled receptor 17 (GPR17) is a stage-specific regulator of oligodendrocyte lineage cell (OLC) differentiation; however, its role in post-SAH remyelination and cognitive recovery remains incompletely understood. This study aimed to elucidate the function of GPR17 in OLCs after SAH and to identify its downstream effector mechanism.

Methods: A mouse model of SAH was established to assess cognitive function, myelin integrity, OLC differentiation, and GPR17 expression. Conditional knockout mice were generated to selectively delete GPR17 in early- or late-stage OLCs. Behavioral tests, histopathological analyses, and myelin-related evaluations were conducted after SAH. Transcriptomic Sequencing was performed to identify downstream signaling pathways regulated by GPR17.

Results: SAH induced a 2.3-fold increase in GPR17+ OLCs at day 7, along with a 42% reduction in mature OLCs and a 41% decrease in MBP expression. Selective deletion of GPR17 in late-stage OLCs-but not in early-stage OLCs-significantly improved cognitive performance after SAH, which was associated with enhanced OLC differentiation and myelin repair. Transcriptomic analysis identified Gelsolin as a critical downstream mediator. Knockdown of Gelsolin abolished the promyelinating and cognitive benefits conferred by late-stage GPR17 deletion.

Conclusion: Stage-specific inhibition of GPR17 in late-stage OLCs promotes remyelination and enhances cognitive recovery after SAH through a Gelsolin-dependent mechanism. The GPR17/Gelsolin signaling pathway represents a promising therapeutic target for post-SAH cognitive impairment.

Keywords
GPR17; Gelsolin; Myelin sheath; Oligodendrocyte lineage cell; Subarachnoid hemorrhage.
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