Restricted accessResearch articleFirst published online 2026-2
Triggering Receptor Expressed on Myeloid Cell 2-Mediated Microglial Phagocytosis in the Subacute Phase of Traumatic Brain Injury Exacerbates Impaired Memory
Traumatic brain injury (TBI) induces severe neuropsychiatric complications. Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for microglial-mediated synaptic engulfment. This study aimed to clarify the unique role played by microglial TREM2 in memory dysfunction during the subacute phase of TBI. Behavior tests were conducted to assess post-TBI memory impairment in male Sprague-Dawley (SD) rats. The activity of microglia in different phases of TBI was observed via detecting Iba1 immunoreactivity by immunofluorescence and microglial markers by quantitative reverse transcription polymerase chain reaction. Pharmacological inhibition of microglia regulates its activity during the subacute phase. Additionally, we employed male Trem2 knockout mice in the C57BL/6J genetic background, as well as male wild-type C57BL/6J mice subjected to brain stereotaxic injection of TREM2 small interfering RNA. Rats subjected to TBI showed impaired memory retention in the Morris water maze test. Microglia activation and TREM2 expression peaked in the subacute phase, especially in Cornu Ammonis1 (CA1). Pharmacological inhibition of microglia in SD rats attenuated cell apoptosis and synaptic loss caused by TBI. Further studies demonstrated that selective knockdown of TREM2 in CA1 reduced microglia-mediated phagocytosis of synapses and enhanced synaptic plasticity, improving memory dysfunction associated with TBI. Our findings suggest that upregulation of TREM2 exacerbated TBI-induced memory dysfunction by promoting excessive microglial phagocytosis and synaptic loss in the subacute phase.
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