Supersensitive presynaptic dopamine D2 receptor inhibition of the striatopallidal projection in nigrostriatal dopamine-deficient mice

The dopamine (DA) D2 receptor (D2R)-expressing medium spiny neurons (D2-MSNs) in the striatum project to and inhibit the GABAergic neurons in the globus pallidus (GP), forming an important link in the indirect pathway of the basal ganglia movement control circuit. These striatopallidal axon terminals express presynaptic D2Rs that inhibit GABA release and thus regulate basal ganglion function. Here we show that in transcription factor Pitx3 gene mutant mice with a severe DA loss in the dorsal striatum mimicking the DA denervation in Parkinson's disease (PD), the striatopallidal GABAergic synaptic transmission displayed a heightened sensitivity to presynaptic D2R-mediated inhibition with the dose-response curve shifted to the left, although the maximal inhibition was not changed. Functionally, low concentrations of DA were able to more efficaciously reduce the striatopallidal inhibition-induced pauses of GP neuron activity in DA-deficient Pitx3 mutant mice than in wild-type mice. These results demonstrate that presynaptic D2R inhibition of the striatopallidal synapse becomes supersensitized after DA loss. These supersensitive D2Rs may compensate for the lost DA in PD and also induce a strong disinhibition of GP neuron activity that may contribute to the motor-stimulating effects of dopaminergic treatments in PD.