ROLE OF MGLUR2 IN PSYCHEDELIC NEURAL AND BEHAVIORAL PLASTICITY

With growing interest in psychedelics as therapeutics for mental health conditions, it is critical to understand the molecular mechanisms underlying their hallucinogenic, behavioral, and neuroplastic effects. While 5-HT_2AR agonism is a defining characteristic of classical psychedelics and mediates their hallucinogenic effects, additional receptors may also contribute to their hallucinogenic and/or post-acute outcomes. The metabotropic glutamate receptor 2 (mGluR2) is an underexplored mediator of psychedelic signaling that is necessary for the hallucinogenic effects of classical psychedelics, and functionally crosstalks with the 5-HT_2AR via receptor heteromerization in frontal cortex pyramidal neurons (FCPNs). Our goal is to understand the role of mGluR2 in the behavioral and neuroplastic effects of the psychedelic 5-HT_2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)−2-aminopropane (DOI), focusing on fear-related behavior and dendritic spine remodeling 24 hours after treatment. Male and female wildtype (WT), global mGluR2 knockout (KO), and pyramidal neuron conditional mGluR2 KO (cKO) mice – with and without DOI treatment – were assessed using head twitch response (HTR) assay, open field test (OFT), and fear acquisition and extinction. To quantify structural plasticity in FCPNs, mice received HSV GFP for dendritic spine analysis. DOI-, genotype and sex-dependent effects were observed across HTR, OFT, and fear extinction measures, indicating the mGluR2 regulates basal locomotor activity and modulates DOI-induced hallucinogenic-like behavior and fear extinction in a sex-dependent manner. These data confirm mGluR2 is required for DOI-induced HTR and provide new evidence that mGluR2 signaling contributes to DOI-mediated facilitation of fear extinction, with effects that appear to be male-specific.