Loss of TREM2 is associated with altered microglial responses and inhibitory synaptic changes after closed head injury.

Closed head injury (CHI) is often considered to cause mild brain injury without overt cortical lesions. However, synaptic pathology following CHI, particularly in different phase, remains poorly understood. In this study, we investigate temporal changes in synaptic protein expression and microglial responses following CHI. Our results show a selective loss of inhibitory presynaptic marker vGAT, accompanied by transient increases in excitatory postsynaptic markers PSD-95 and gephyrin. Notably, these changes occur alongside a peak in microglial activation at 3 days post-injury (dpi). Bulk RNA sequencing analysis identified TREM2 as a prominently upregulated microglia-associated gene during the acute phase of injury. Loss of TREM2 in knockout mice (TREM2-/-) resulted in attenuated microglial activation, impaired accumulation at the injury site, and reduced expression of response-related genes, including Cx3cr1 and Cd68. Additionally, C1q, a key component in synaptic pruning, exhibited altered expression and spatial distribution in TREM2-deficient mice, suggesting a potential TREM2-dependent role in regulating microglial responses and synaptic alterations after CHI. These findings highlight TREM2 as a critical modulator of microglial function and synaptic remodeling following brain injury.