The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Introduction

Cortical atrophy and dysfunction are central features of many neuropsychiatric disorders, and small molecules called psychoplastogens can rapidly promote structural and functional neuronal growth in the prefrontal cortex (PFC). Classic serotonergic psychedelics (for example, psilocybin, LSD, 5-MeO) are potent psychoplastogens but their profound subjective effects limit clinical scalability. Nonhallucinogenic psychoplastogens structurally related to psychedelics, such as tabernanthalog (TBG), have been developed as potential alternatives that might stimulate similar plasticity without producing hallucinatory effects. Aarrestad and colleagues set out to test whether TBG promotes cortical neuroplasticity via the same intracellular signalling pathway attributed to classic psychedelics (involving 5-HT2A receptors, TrkB, mTOR and AMPA receptors), and whether immediate early gene (IEG) induction and acute glutamate bursts are required for psychoplastogen-induced spinogenesis and antidepressant-like behaviour. The study uses complementary pharmacological and genetic tools in rodents, in vitro assays and in vivo imaging to compare TBG with hallucinogenic congeners and to map acute neuronal activity and gene-expression responses associated with each compound.