Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice

Degeneration of dopamine (DA) neurons in Parkinson’s disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy. •Dopamine denervation enables sensitized striatonigral-mediated motor activation•Dopamine denervation leads to increased striatonigral synaptic activity•Striatonigral GABA release is controlled by GABAB autoreceptors•Dopamine denervation disrupts normal GABAB-mediated control of striatonigral activity In Parkinson’s disease patients, dopamine replacement therapy eventually triggers sensitized and uncontrolled motor responses. Borgkvist et al. reveal a dopamine-independent role for elevated presynaptic transmission at striatonigral GABA synapses in parkinsonian motor sensitization.