Glutamatergic Neurons in the Caudal Zona Incerta Regulate Parkinsonian Motor Symptoms in Mice.

Parkinson's disease (PD) is the second most common and fastest-growing neurodegenerative disorder. In recent years, it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis. However, little is known about whether and how the caudal zona incerta (ZIc) regulates parkinsonian motor symptoms. Here, we showed that specific glutamatergic but not GABAergic ZIcVgluT2 neurons regulated these symptoms. ZIcVgluT2 neuronal activation induced time-locked parkinsonian motor symptoms. In mouse models of PD, the ZIcVgluT2 neurons were hyperactive and inhibition of their activity ameliorated the motor deficits. ZIcVgluT2 neurons monosynaptically projected to the substantia nigra pars reticulata. Incerta-nigral circuit activation induced parkinsonian motor symptoms. Together, our findings provide a direct link between the ZIc, its glutamatergic neurons, and parkinsonian motor symptoms for the first time, help to better understand the mechanisms of PD, and supply a new important potential therapeutic target for PD.