Mechanism of METTL3‐mediated m6A modification in depression‐induced cognitive deficits

Depressive disorder (DD) is associated with N6‐methyladenosine (m6A) hypermethylation. This study sought to explore the molecular mechanism of Methyltransferase‐like 3 (METTL3) in cognitive deficits of chronic unpredictable mild stress (CUMS)‐treated rats and provide novel targets for DD treatment. A DD rat model was established via CUMS treatment. Cognitive deficits were assessed via body weighing and behavioral tests. METTL3, microRNA (miR)‐221‐3p, pri‐miR‐221, GRB2‐associated binding protein 1 (Gab1) expressions in hippocampal tissues were detected via RT‐qPCR and Western blotting. m6A, DiGeorge syndrome critical region gene 8 (DGCR8)‐bound pri‐miR‐221 and pri‐miR‐221 m6A levels were measured. The binding relationship between miR‐221‐3p and Gab1 was testified by dual‐luciferase and RNA pull‐down assays. Rescue experiments were designed to confirm the role of miR‐221‐3p and Gab1. METTL3 was highly expressed in CUMS rats, and silencing METTL3 attenuated cognitive deficits of CUMS rats. METTL3‐mediated m6A modification facilitated processing and maturation of pri‐miR‐221 via DGCR8 to upregulate miR‐221‐3p. miR‐221‐3p targeted Gab1. miR‐221‐3p overexpression or Gab1 downregulation reversed the role of silencing METTL3 in CUMS rats. Overall, METTL3‐mediated m6A modification facilitated processing and maturation of pri‐miR‐221 to upregulate miR‐221‐3p and then inhibit Gab1, thereby aggravating cognitive deficits of CUMS rats.