The ?2A-adrenergic receptor (?2AAR) is a prototypical Gi/o-coupled receptor, and mediates a variety of physiological/pharmacological responses ranging from control of central blood pressure to mediating analgesia to regulating cognitive function. However, our knowledge of ?2AAR-mediated signaling and its regulatory mechanisms at the molecular and cellular levels remains limited, hindering our ability to target this receptor for the design of new therapeutic strategies with improved efficacy and fewer adverse effects. The long-term goal of our studies is to define the molecular/cellular mechanisms whereby ?2AAR functions are regulated, so as to enable the development of novel, effective therapeutic strategies targeting this receptor for disease treatment. Like most Gi/o-coupled receptors, the ?2AAR can be localized in both pre- and postsynaptic compartments, and is well appreciated for its role in inhibition of presynaptic neurotransmitter release. However, how ?2AAR, and Gi/o-coupled receptors in general, regulates postsynaptic signaling remains poorly understood. Our unpublished studies revealed a novel signaling cascade downstream of the postsynaptic ?2AAR involving activation of PTEN and inhibition of Akt in neurons. Furthermore, spinophilin, a postsynaptic protein that can bind to multiple GPCRs, directly mediates ?2AAR-induced PTEN activation. Originally identified as a tumor suppressor, PTEN has recently received increased attention for its roles in regulating neural plasticity and cognitive function. How PTEN activity may be regulated by GPCRs as a means to modulate synaptic plasticity and cognition remains largely unexplored. Hence, spinophilin-dependent PTEN activation provides a novel mechanism by which postsynaptic GPCRs can modulate synaptic plasticity and cognition. Furthermore, targeting postsynaptic scaffolding proteins such as spinophilin represents an attractive strategy to specifically manipulate the postsynaptic function of the Gi/o-coupled receptors for disease treatment. The primary objective of this proposal is to uncover the essential role of spinophilin in mediating ?2AAR-induced PTEN/Akt signaling and explore the spinophilin-mediated regulation as a target for ameliorating ?2AAR-elicited cognitive impairment. In Aim 1, we will determine how spinophilin scaffolds a multi-protein complex to mediate ?2AAR- induced PTEN activation. In Aim 2, we will determine the functional consequence of spinophilin-dependent PTEN activation upon ?2AAR stimulation on Akt/mTOR signaling and local protein synthesis. In Aim 3, we will determine the in vivo relevance of spinophilin regulation of ?2AAR-induced PTEN/Akt signaling by assessing behavioral effects. Elevated ?2AAR expression/activity has been associated with neuropsychiatric disorders such as major depression and ADHD. Accomplishing this proposal will advance our fundamental knowledge of how postsynaptic Gi/o-coupled receptors, particularly ?2AAR, may regulate neural plasticity and cognitive functions. Furthermore, our studies will provide necessary information for future design of therapeutics for neuropsychiatric diseases in which altered ?2 adrenergic signaling plays a role.