A paradigm shift of SERPINA3N in neurobehavioral development and brain injury

Murine serine protease inhibitor clade A member 3N (SERPINA3N) and its human ortholog SERPINA3 are dysregulated in neurological disorders. SERPINA3N has been proposed as a protective factor, enhancing neurobehavioral development under homeostasis and mitigating neuronal/glial and vascular damage under neurological conditions. Here, we employed powerful, non-invasive genetic tools to revisit the concept of SERPINA3N in brain development and injury. Brain-specific SERPINA3N overexpression neither alters neuronal or glial development nor improves cognitive ability under homeostasis. In stark contrast, SERPINA3N drives a pro-inflammatory response to brain injury and exacerbates blood-brain barrier dysfunction. Its overexpression promotes neurodegeneration through apoptosis-mediated neuronal loss and disrupts oligodendroglial differentiation and myelination following neonatal brain injury. Collectively, our findings challenge the prevailing paradigm of SERPINA3N in neurodevelopment and injury, revealing that while SERPINA3N is dispensable for neurobehavioral development, it aggravates neural injury and vascular damage under pathological conditions.