Serotonin and glutamate interactions in preclinical schizophrenia models

The serotonergic and glutamatergic neurotransmitter systems have both been implicated in the pathophysiology of schizophrenia, and there are multiple lines of evidence to demonstrate that they can interact in a functionally relevant manner. Particularly, it has been demonstrated that serotonin (5-hydroxytryptamine) 2A (5-HT_2A) receptors and metabotropic glutamate type 2 (mGlu2) receptors can assemble into a functional heteromeric complex and modulate each other's function. This heteromeric complex has been implicated in the mechanism of action of hallucinogens as well as antipsychotic agents, and its role has been demonstrated in both in vitro and in vivo systems. Additionally, the difference in the changes in G_i/o and G_q/11 protein activity when a ligand binds to the heteromeric complex can be used as an index to predict the pro- or antipsychotic properties of an agent. Signaling via the heteromer is dysregulated in postmortem human brain samples of schizophrenia subjects, which may be linked to altered cortical functions. Alternative routes for the functional crosstalk between mGlu2 and 5-HT_2A receptors include synaptic and epigenetic mechanisms. This Review highlights the advances made over the past few years in elucidating the structural and functional mechanisms underlying crosstalk between 5-HT_2A and mGlu2 receptors in preclinical models of schizophrenia.