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.
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and.
Wei
W
Wei
Li
L
Li
Guoliang
G
Yu
Shengyuan
S
Ding
Chengyao
C
Li
Fu-Ming
FM
Zhou
D000200:Action Potentials; D000818:Animals; D004298:Dopamine / Q000172:deficiency* / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D005917:Globus Pallidus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D053444:Inhibitory Postsynaptic Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
D018398:Homeodomain Proteins; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; C433629:homeobox protein PITX3; D004298:Dopamine
Parkinson's disease; basal ganglia; dopamine receptor; globus pallidus; presynaptic inhibition