Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease (PD). To investigate the pathogenic mechanism, researchers generated a mouse model with a germline disruption in parkin. Parkin^-/- mice are viable and have normal brain morphology. Quantitative in vivo microdialysis showed increased extracellular dopamine in the striatum. Intracellular recordings of striatal spiny neurons indicated reduced synaptic excitability. Parkin^-/- mice showed behavioral deficits sensitive to nigrostriatal dysfunction, but dopaminergic neurons in the substantia nigra remained normal up to 24 months. Steady-state levels of parkin substrates, including CDCrel-1, synphilin-1, and α-synuclein, were unchanged in parkin^-/- brains. These findings suggest a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role in the survival of nigral neurons. Parkinson's disease is an age-related movement disorder characterized by bradykinesia, rigidity, and dopamine depletion in the striatum. The loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies are hallmarks of PD. Parkin is widely expressed in brain and heart, and functions as an E3 ubiquitin ligase. The study shows that parkin^-/- mice have increased extracellular dopamine in the striatum, reduced synaptic excitability, and behavioral deficits, but no loss of dopaminergic neurons. These results indicate that parkin loss-of-function mutations cause defects in dopamine release and synaptic excitability, which are major targets of nigral dopaminergic projections. The findings provide important insights into the normal physiological role of parkin in dopamine regulation and nigrostriatal function, which may assist in identifying novel preventative and therapeutic strategies for PD.Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease (PD). To investigate the pathogenic mechanism, researchers generated a mouse model with a germline disruption in parkin. Parkin^-/- mice are viable and have normal brain morphology. Quantitative in vivo microdialysis showed increased extracellular dopamine in the striatum. Intracellular recordings of striatal spiny neurons indicated reduced synaptic excitability. Parkin^-/- mice showed behavioral deficits sensitive to nigrostriatal dysfunction, but dopaminergic neurons in the substantia nigra remained normal up to 24 months. Steady-state levels of parkin substrates, including CDCrel-1, synphilin-1, and α-synuclein, were unchanged in parkin^-/- brains. These findings suggest a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role in the survival of nigral neurons. Parkinson's disease is an age-related movement disorder characterized by bradykinesia, rigidity, and dopamine depletion in the striatum. The loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies are hallmarks of PD. Parkin is widely expressed in brain and heart, and functions as an E3 ubiquitin ligase. The study shows that parkin^-/- mice have increased extracellular dopamine in the striatum, reduced synaptic excitability, and behavioral deficits, but no loss of dopaminergic neurons. These results indicate that parkin loss-of-function mutations cause defects in dopamine release and synaptic excitability, which are major targets of nigral dopaminergic projections. The findings provide important insights into the normal physiological role of parkin in dopamine regulation and nigrostriatal function, which may assist in identifying novel preventative and therapeutic strategies for PD.