7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress.

RATIONALE: 7-Chlorokynurenic acid (7-CTKA), a NMDA receptor antagonist, has been reported as a potential rapid antidepressant with poor understanding about the molecular mechanism of its therapeutic action. MicroRNAs (miRNAs) are emerging as critical regulators of central nervous system plasticity and may play an important role in depression.
OBJECTIVE: The objective of this study was to investigate the molecular mechanism of antidepressant action of 7-CTKA in chronic unpredictable mild stress (CUMS) animal model.
METHODS: K252a (tropomyosin-related kinase receptor B (TrkB) antagonist), U0126 (extracellular signal-regulated kinase (ERK) phosphorylation inhibitor), LY294002 (serine-threonine kinase (Akt) phosphorylation inhibitor), or vehicle was given intracerebroventricularly to mice in each group 30 min before 7-CTKA or vehicle intraperitoneal injection. Behavioral changes were observed by sucrose preference test and miRNA microarray was performed to examine hippocampal miRNAs levels in mice. Quantitative RT-PCR was conducted to further confirm results in microarray study.
RESULTS: 7-CTKA not only reversed the decrease in sucrose preference and multiple hippocampal miRNAs changes induced by CUMS but also mediated 15 common miRNAs via TrkB-ERK/Akt pathways. Among them, the expression levels of four miRNAs (miR-34a-5p, miR-200a-3p, miR-144-3p, miR-1894-5p) were validated by quantitative real-time PCR (qRT-PCR). The findings from qRT-PCR study support results from microarray analysis except for the non-significance of miR-1894-5p expression.
CONCLUSIONS: This demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA.