A genetically encoded fluorescent sensor called psychLight, based on the 5-HT2A receptor structure, detects behaviorally relevant serotonin release and correctly predicts whether structurally similar 5-HT2AR ligands will cause hallucinogenic behavioral effects. Using psychLight, a non-hallucinogenic psychedelic analog was identified that produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The sensor enables in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and development of non-hallucinogenic therapeutics targeting the 5-HT2AR.
Serotonin (5-HT) is a key neuromodulator that directly influences plasticity at excitatory synapses on dendritic spines. It activates 14 subtypes of G-protein-coupled receptors, each with distinct expression and signaling. Disruptions in serotonergic transmission during development or adulthood cause lasting changes in behavior and neuronal structure, particularly in dendritic spines, indicating serotonin's critical role in excitatory synaptic plasticity. This review summarizes how 5-HT receptors contribute to the development and maturation of excitatory postsynaptic synapses, from spinogenesis through stabilization, potentiation, and depression. It also highlights recent advances showing how atypical serotonergic signaling and psychedelics alter spine structure and function.