It's finally here! Years in the making and going through a good portion of the review process during #COVID19! Our study on the #mechanism of #ketamine's #antidepresseant effect out today @nature @CarletonScience @mcgillu @uMontreal_news 1/n
https://www.nature.com/articles/s41586-020-03047-0 1/n

#Ketamine has offered new hope for #treatmentresistant people with #depression. But how does it work? Pivotal work from Ron Duman’s lab indicated that mTOR was involved. Lisa Monteggia’s group also demonstrated that protein synthesis was required. Through which mediator? 2/n

So, we looked at the 4E-BPs, crucial regulators of the mRNA translation process, regulated by mTORC1. The absence of either 4E-BP1 or 4E-BP2 (2 of the 3 isoforms in mammals) blocked the effect of ketamine on behaviour and potentiation of hippocampal synaptic transmission. 3/n

Importantly, although both 4E-BP1 and 4E-BP2 were required for these effects, there was a more generalized requirement for the 4E-BP2 isoform. But not only for ketamine, but also for hydroxynorketamine, a metabolite of ketamine that has anti-depressant effects in mice. 4/n

Then, we investigated whether this effect was occurring in excitatory or inhibitory neurons. Knocking out either 4E-BP1 or 4E-BP2 in excitatory neurons blocked the effect of ketamine, as it has been previously suggested. 5/n

Surprisingly though, the effect was more striking when mRNA translation was blocked in inhibitory neurons, which also blocked the potentiation of excitatory synaptic currents!! 6/n

Huge thanks to our collaborators: Danilo de Gregorio @EdnaMattaC Mohammad Elasmizade @abde13015 @abskalecka Martha Lopez Canul @angelica_atb Sara Bermudez, @stephaniearay19 @garjeanr @SalmasoLab Gabriella Gobbi, Jean-Claude Lacaille & Nahum Sonenberg

This work was a collaboration between @McGillGCRC @McGillMedPsych @UMontreal @CarletonScience @NeuroCarleton

We also thank the funding agencies @CIHR_IRSC @FRQS1 for their support through these years.

@CAN_ACN