Chronic stress reduces reelin, a brain protein, in the hippocampus and causes depression-like behavior. A single dose of reelin or ketamine each reversed these behavioral and molecular effects within one hour, and the benefit lasted at least one week. When given together, reelin and ketamine showed additive effects after one week. The findings suggest that reelin-based treatments could become a new class of rapid-acting antidepressants.
In neurons derived from induced pluripotent stem cells of five women with treatment-resistant depression (average age 40.2 years), both the glycoprotein reelin and the ketamine metabolite (2R,6R)-hydroxynorketamine increased expression of several synaptic proteins (GluA1, PSD-95, Dab1, Synapsin I, and p-ERK) within one hour, with effects declining by 24 hours. Gene expression changes were similar for both compounds, though only reelin upregulated mTORC1 signaling. The findings suggest that iPSC-derived neurons may serve as a useful in vitro model for studying treatment-resistant depression and testing potential therapeutics.