Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. The core motor symptoms of PD are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Why SNc DA neurons die in PD has been an enduring mystery. In the last grant period, we made significant progress toward identifying characteristics of these neurons that could lead to their accelerated aging, dysfunction and death. These studies suggest that the selective vulnerability of SNc DA neurons in PD is linked to their reliance upon Cavi.3 Ca2+ channels to i) drive autonomous pacemaking and 2) generate spike bursts in response to synaptic stimulation. More importantly from the the therapeutic standpoint, we discovered that this reliance upon Cavi.3 channels could be diminished by systemic administration of a drug that is approved for human use in the treatment of hypertension. In a murine model, treatment with this drug led to significant protection of SNc DA neurons against rotenone toxicity in vitro and against 6-OHDA and MPTP in vivo. The central aim of this project is to determine the mechanisms underlying these observations and to lay the foundation for translating these bench discoveries into a plan for clinical neuroprotection trials in humans. Using the most advanced optical, electrophysiological and molecular tools available, our interdisciplinary research team (Drs. Surmeier, Wilson, Bevan and Osten) will pursue four specific aims: 1) to characterize the interaction between mitochondria and the Ca24 that enters SNc DA neurons during pacemaking (Surmeier, Wilson). 2) to characterize the impact of glutamatergic synaptic input on mitochondrial function during pacemaking in SNc DA neurons (Bevan, Surmeier, Osten) 3) to characterize the mechanisms underlying the reversion of pacemaking in SNc DA neurons following sustained block of Cavi.3 channels (Surmeier, Osten). 4) to explore novel neuroprotective strategies targeting Cavi.3 channels in SNc DA neurons that could be translated to human clinical trials (Surmeier, Osten). The successful attainment of these aims will move us closer to clinical neuroprotection trials and provide needed insight into the cellular and molecular mechanisms underlying the loss of SNc DA neurons in PD. Lay summary: Understanding why neurons die in PD will help us stop the disease. These studies take the steps necessary to bring a novel neuroprotective therapy to the clinic in the near term.