Poster 31 Opioid Modulation of Inhibitory Synapses in Striatal Patch Compartments Matthew R. Banghart, Shay Q. Neufeld, Bernardo L. Sabatini Howard Hughes Institute, Dept. of Neurobiology, Harvard Medical School, Boston, USA Opioid peptides and their receptors are prominent in the dorsal striatum, a brain region critical for the generation of purposeful movements and goal-directed behavior. The mu-opioid receptor (MOR) is highly enriched in striatal patch compartments, which are distinct limbic microcircuits embedded within the sensorimotor dorsal striatum. Previous work has revealed patch-specific suppression of inhibition by the MOR agonist DAMGO, but the pre- and post-synaptic neurons that are modulated remain unknown1. Furthermore, enkephalin, which activates both MOR and the delta-opioid receptor (DOR), is the apparent native ligand for MOR in striatum. The role of this endogenously occurring peptide in opioidergic modulation in patches remains completely unexplored. Using slice electrophysiology in tissue from transgenic mice in combination with optogenetics and photoactivatable peptides, we identified the inhibitory synapses suppressed by opioid peptides, mapped the underlying receptors, and defined the kinetics of modulation. We first validated a transgenic mouse line that allows simultaneous observation of patches and postsynaptic cell identity. We confirmed that enkephalin suppresses local inhibition onto both direct and indirect pathway striatal projection neurons selectively in patches. To determine the synaptic targets of enkephalin we conditionally expressed ChR2 in specific cell types and found that particular subsets of inhibitory synapses were suppressed. Investigation of the underlying receptors revealed that although MOR contributes to the suppression of inhibition, DOR also plays a major role. We further investigated the cellular locus of each receptor and their dependence on PKA signaling. Finally, we probed the time course of opioid peptide modulation with caged enkephalin2, allowing instantaneous delivery of saturating peptide concentrations. To our surprise, maximal synaptic suppression required the presence of peptide for several minutes. These results delineate how opioid release in striatum could shift the balance of limbic-associated striatal output by suppressing a subset of inhibitory synapses in patches. 1. Miura M., Saino-Salto S., Masuda M., Kobayashi K. and Aosaki T. J Neurosci 27(36): 972128 (2007) 2. Banghart M.R. and Sabatini B.L. Neuron 73(2): 249-59 (2012) Funding: This work was supported by the Charles A. King Trust (MRB), the National Institute on Drug Abuse (K99DA034648 to MRB), the Canadian Institute of Health Research (SQN), the National Institute of Mental Health (RO1MH085418&R01MH100568 to BLS), and the Howard Hughes Medical Institute (BLS).