Endothelial miR-15a/16-1 regulation of Syne1 mediates structural and functional recovery after traumatic brain injury

Although miR-15a/16-1 deletion has recently been shown to be neuroprotective in brain injury, the endothelial pathways mediating long-term structural and functional recovery after TBI remain unknown. Here, we demonstrate endothelial-specific deletion of miR-15a/16-1 is sufficient to confer neurorestoration after TBI by reducing acute BBB leakage, preserving white and gray matter integrity, and accelerating sensorimotor and cognitive recovery.

Mechanistically, transcriptomic profiling identified Syne1 as a direct downstream target of miR-15a/16-1, validated via in-silico binding prediction and 3’-UTR luciferase assays. Crucially, endothelial cells-targeted AAV-mediated knockdown of Syne1 abrogated the neurorestorative effects of miR-15a/16-1 deletion, indicating Syne1 is required for its function. Furthermore, single-cell RNA-seq analysis of human TBI tissue demonstrates significant downregulation of Syne1 in endothelial cells within the contusion core relative to pericontusional endothelium.