Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons.

Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear.

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.

Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway-involving 5-HT, TrkB, mTOR and AMPA receptor activation-as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG.