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bioRxiv · 10.1101/2022.04.06.487292

Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons

Cannarozzo, C.·Rubiolo, A.·Casarotto, P. C.·Castren, E.
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Abstract

Ketamine 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 3 injections, throughout the 8-days regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared to 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 (PTP{sigma}), 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 PTP{sigma} regulation, without necessarily affecting PNNs deposits.

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Cannarozzo, C., Rubiolo, A., Casarotto, P. C., Castren, E.. 2022-04-09. Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons. https://doi.org/10.1101/2022.04.06.487292

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