Trans-synaptic control of GPCR signaling in opioid reward

PROJECT SUMMARY Opioids exert their addictive effects by altering signal processing in the reward circuit of the basal ganglia. This action involves multiple adaptations, including changes in neuronal wiring and synaptic transmission. Recent evidence suggests that the glutamatergic system plays a critical role in reward. Particularly, group III metabotropic glutamate receptors (mGluRs) have been recognized for their role in shaping opioid effects Located at presynaptic terminals of neurons, group III mGluRs control the strength of glutamatergic actions and synaptic plasticity of the reward circuit. The overall goal of this research is to understand molecular mechanisms by which opioids alter glutamatergic signaling and wiring of the reward circuit. The focus of this proposal is on ELFN1, a recently discovered cell-adhesion molecule which interacts with group III mGluRs, modulates their function and plays a key role in establishing synaptic connectivity. ELFN1 is selectively expressed in cholinergic interneurons (CIN) in the reward circuit hub – nucleus accumbens (NAc) and its ablation in mice prominently influences opioid effects. Based on accumulated preliminary data, we hypothesize that the trans-synaptic interaction of ELFN1 in CIN with group III mGluRs on glutamatergic afferents in the NAc plays a critical role in the structural and functional plasticity of synaptic communication in the reward circuit to shape opioid effects. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) elucidate the physiological role of ELFN1 in specifying synaptic properties of NAc neurons, (2) determine molecular mechanisms of ELFN1 action and (3) characterize the contribution of ELFN1-mGluR complexes to rewarding effects of opioids. The strategy proposed to address these Aims will entail a synergistic combination of behavioral, genetic, cell-biological, and physiological approaches, exploiting a powerful array of reagents, animal models, and innovative assays to examine role and mechanisms of ELFN1 in the endogenous setting of a nervous system. Such studies are expected to provide critical insights into the role of synaptic cell adhesion molecules in configuring neural circuitry and neuromodulatory receptors involved in reward processing and opioid use disorder.