Neuron-specific deficiency of autophagy increases neuronal loss in traumatic brain injury

The involvement of neuronal autophagy in traumatic brain injury (TBI) remains elusive. Previous investigations, as far as our knowledge extends, have modulated autophagy either through systemic administration of autophagy inhibitors/inducers or by eliminating key regulators of autophagy across all somatic cells, lacking specificity for neurons. Consequently, drawing conclusions from such studies may be muddled by inhibiting autophagy in other cell types, including astrocytes, microglia, and immune cells. To discern the precise role of neuronal autophagy in TBI, we generated tamoxifen-induced, neuron-specific, autophagy-deficient mice by crossing <i>atg5</i> ^flox/flox mice with <i>map2</i>-CreER^T2 mice. We then induced TBI in either control mice or mice with neuron-specific autophagy deficiency. Our findings revealed that the absence of autophagy, specifically in adult neurons, led to exaggerated neurologic-deficit syndromes and more pronounced neuronal loss. Additionally, we demonstrated that neuronal autophagy is orchestrated by immunity-related GTPase family M member 1 (Irgm1) in neural injury, as evidenced by neuron-specific <i>irgm1</i> knockout mice displaying a significant reduction in neuronal autophagy and heightened neuronal loss compared with control mice. Collectively, our data provide more conclusive evidence that fortifies the neuroprotective role of autophagy in TBI.