Ketamine and its metabolite 2R,6R‐hydroxynorketamine promote ocular dominance plasticity and release tropomyosin‐related kinase B from inhibitory control without reducing perineuronal nets enwrapping parvalbumin interneurons

Abstract

AbstractKetamine has been described as a fast‐acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R‐hydroxynorketamine (R,R‐HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R‐HNK facilitated the shift in ocular dominance in monocularly deprived mice, after three injections, throughout the 7‐day monocular deprivation regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R‐HNK compared with ketamine. Treatment with ketamine or R,R‐HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin‐positive interneurons. However, we observed in vitro that both ketamine and R,R‐HNK are able to disrupt the tropomyosin‐related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTPσ), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile‐like plasticity by directly binding TRKB and releasing it from PTPσ regulation, without necessarily reducing PNNs deposits.