Past events

: G-protein coupled receptors (GPCRs) play a paramount role in diverse brain functions. Twenty years ago, GPCR activity was shown to be regulated by membrane potential in vitro, but whether the voltage dependence of GPCRs contributes to neuronal coding and behavioral output under physiological conditions in vivo has never been demonstrated. We show in two different processes that muscarinic GPCR mediated neuromodulation in vivo is voltage dependent. First, we show that muscarinic type A receptors (mAChR-A) mediated neuronal potentiation is voltage dependent. This potentiation voltage dependency is abolished in mutant flies expressing a voltage independent receptor. Most important, muscarinic receptor voltage independence caused a strong behavioral effect of increased odor habituation. Second, we show that muscarinic type B receptors (mAChR-B) voltage dependency is required for both efficient and accurate learning and memory. Normally, to prevent non-specific olfactory learning and memory, mAChR-B activity suppress both signals that are required for plasticity. Behavior experiments demonstrate that mAChR-B knockdown impairs olfactory learning by inducing undesired changes to the valence of an odor that was not associated with the reinforcer. On the other hand, mAChR-B voltage dependence prevents mAChR-B to interfere with plasticity in neurons that are required for the learning and memory process. Indeed, generating flies with a voltage independent mAChR-B resulted in impaired learning. Thus, we provide the very first demonstrations of physiological roles for the voltage dependency of GPCRs by demonstrating crucial involvement of GPCR voltage dependence in neuronal plasticity and behavior. As such, our findings create a paradigm shift in our thinking on GPCR recruitment and activity. Together, we suggest that GPCR voltage dependency plays a role in many diverse neuronal functions including learning and memory and may serve as a target for novel drug development. Light refreshments before the seminar.