Decreased TREM2 expression in prefrontal cortex induces cognitive impairment and sensorimotor gating deficits in schizophrenia

Multiple lines of evidence indicate the implication of neuroinflammatory processes in the pathophysiology of schizophrenia. Microglia are brain resident immune cells and have been implicated in schizophrenia pathogenesis as their aberrant activation is one of the leading hypotheses. However, due to the limited availability proper human cell models, the role of microglia in schizophrenia is largely unknown. In this study, we applied an established differentiation model to induce microglia-like (iMG) cells from 28 patients with recent-onset schizophrenia and 18 healthy controls to analyse molecular and functional alterations in myeloid cells in schizophrenia. We found that the expression of the microglial marker triggering receptor expressed on myeloid cells 2 (TREM2) was significantly reduced in iMG cells derived from patients with schizophrenia (P < 0.05). We constructed a murine model with Trem2 knockdown in the medial prefrontal cortex (mPFC) using stereotaxic injection of adeno-associated virus (AAV). Mice with Trem2 knockdown in the mPFC (Trem2-shRNA) exhibited impaired cognition and disrupted sensorimotor gating. In addition, compared with controls, Trem2-shRNA mice exhibited a distinct pro-inflammatory cytokine profile, with significantly increased mRNA expression of IL-6 and TNF-α and decreased expression of IL-10 (P < 0.05). Finally, we revealed a potential mechanism by which downregulation of TREM2 affects glutamate metabolism dysfunction involved in the pathogenesis of schizophrenia. Taken together, our results suggest that downregulation of the Trem2 gene in the mPFC may induce schizophrenia-like behaviours in mice and demonstrate that TREM2 may play crucial roles in the pathogenesis of schizophrenia.