LAUSR

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has recently been suggested to exert fast-acting antidepressant-relevant actions and was proposed as an ideal next-generation antidepressant. However, the microRNA-mediated mechanism underlying its effects is still unknown. In the present study, we investigated the role of miR-34a in the prelimbic (PL) cortex during (2R,6R)-HNK-mediated antidepressant-like effects. Male (8-10 weeks old) C57BL/6J mice and primary hippocampal cultured neurons were employed. The tests of forced swimming, tail suspension, sucrose preference, and female urine sniffing were used as indices of depressive-like behaviors. (2R,6R)-HNK enhanced miR-34a levels in a time-dependent manner at 1, 24 h, and 3 days in vitro, in a time-dependent manner at 1 and 24 h, and in a dose-dependent manner at 10 and 30 mg/kg in PL. Pretreatment with NBQX or verapamil blocked (2R,6R)-HNK-enhanced miR-34a expression and NBQX pretreatment blocked AMPA-elevated miR-34a levels in vitro. AAV-miR-34a in PL produced antidepression-behavioral effects and rescued stress-induced depressive-like behaviors. Moreover, PL AAV-miR-34a increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and potentiated evoked excitatory postsynaptic currents (EPSCs). Slices incubated with miR-34a mimic acutely enhanced the frequency and amplitude of mEPSCs in the PL. Intra-PL application of miR-34a rapidly produced antidepression-like effects and reversed stress-evoked depressive-like behaviors. Furthermore, intra-PL application of anti-miR-34a attenuated both systemic and local (2R,6R)-HNK-mediated antidepressant-like actions. Collectively, these results suggest that miR-34a in PL plays an antidepression-like role and contributes to the fast-acting antidepressant-relevant actions of (2R,6R)-HNK. The present study provides evidence for a miR-34a-dependent mechanism underlying the fast-acting antidepressant-like actions of (2R,6R)-HNK, indicating a novel role of PL miR-34a in antidepression.