5-MeO-DMT induces NEIL3-independent acute cell proliferation in the adult dentate gyrus

Abstract Adult dentate gyrus neurogenesis and cell proliferation are regulated by multiple physiological inputs, including experience-dependent signals that have been linked to the DNA glycosylase NEIL3. Whether NEIL3 also gates psychedelic-induced proliferation is unknown. Here we tested the effect of a single dose of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), a serotonergic agonist with psychedelic properties previously shown to increase dentate gyrus neurogenesis, in wild-type and Neil3 knockout adult mice. Mice received intracerebroventricular 5-MeO-DMT or saline, followed by intraperitoneal BrdU injection. Brains were collected 12 h after BrdU administration, and BrdU-positive cells were quantified in horizontal sections of the ventral dentate gyrus. Baseline BrdU labeling did not differ between genotypes, consistent with NEIL3 being dispensable for naïve-state proliferation. 5-MeO-DMT increased acute BrdU labeling in both wild-type and Neil3 knockout mice, with Neil3 knockout mice exhibiting significantly more BrdU-positive cells than wild-type mice after treatment. These results indicate that NEIL3 is may not be required for the acute proliferative response to 5-MeO-DMT and suggest genotype-dependent modulation of this effect.