Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine...

Treatment-resistant depression (TRD) is associated with worse clinical outcomes and longer course of illness. However, TRD is more difficult to model in animal phenotypes, suggesting that other experimental and translational models must be considered to properly address and research novel therapeutics. Reelin, an endogenous glycoprotein downregulated in depression, has shown rapid antidepressant-like effects akin to those of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine. Interestingly, the antidepressant-like effects of both ketamine and reelin affect mechanistic target of rapamycin complex 1 (mTORC1) activity and that of its related downstream signalers. (2 R,6 R)-hydroxynorketamine (HNK) is a major metabolite of ketamine that, at therapeutic levels, appears to activate mTORC1 without antagonizing NMDARs. To model the effects of (2 R,6 R)-HNK and reelin on neurons from TRD participants, induced pluripotent stem cells (iPSCs) were reprogrammed from peripheral blood mononuclear cells collected from five females with TRD (mean=40.2 yrs) and then differentiated into cortical neurons. In iPSC-derived neurons from TRD participants, 50 nM reelin and 1 µM (2 R,6 R)-HNK had similar effects on the protein expression of GluA1, PSD-95, Dab1, Synapsin I, and p-ERK, with concentration-dependent increases observed at one hour that significantly decreased by 24 h. RNA sequencing revealed similar changes in gene expression between 50 nM reelin and 1 µM (2 R,6 R)-HNK at one hour, although only reelin upregulated mTORC1 signaling. While this work remains preliminary, the results suggest that iPSC-derived neurons could provide a valuable in vitro model to study TRD and hold promise for evaluating novel therapeutics such as (2 R,6 R)-HNK and reelin.Clinicaltrials.gov: NCT02484456.