title: Dopaminergic treatment weakens medium spiny neuron collateral inhibition in the parkinsonian striatum.
abstract: The striatal medium spiny neurons (MSNs) are critical to both motor and cognitive functions. A potential regulator of MSN activity is the GABAergic collateral axonal input from neighboring MSNs. These collateral axon terminals are further under the regulation of presynaptic dopamine (DA) receptors that may become dysfunctional when the intense striatal DA innervation is lost in Parkinson's disease (PD). We show that DA D1 receptor-expressing MSNs (D1-MSNs) and D2 receptor-expressing MSNs (D2-MSNs) each formed high-rate, one-way collateral connections with a homotypic preference in both normal and DA-denervated mouse striatum. Furthermore, whereas the homotypic preference, one-way directionality and the basal inhibitory strength were preserved, DA inhibited GABA release at the D2-MSN→D2-MSN collateral synapse in a supersensitive manner in the DA-denervated striatum. In contrast, for D1-MSN-originated collateral connections, whereas D1 agonism facilitated D1-MSN→D1-MSN collateral inhibition in the normal striatum, this presynaptic D1R facilitation of GABA release was lost in the parkinsonian striatum. These results indicate that in the parkinsonian striatum, dopaminergic treatment can presynaptically weaken the D2-MSN→D2-MSN collateral inhibition and disinhibit the surrounding D2-MSNs, whereas the D1-MSN→D1-MSN collateral inhibition is weakened by the loss of the presynaptic D1 receptor facilitation, disinhibiting the surrounding D1-MSNs. Together, these newly discovered effects can disrupt the MSN circuits in the parkinsonian striatum and may contribute to dopaminergic treatment-induced aberrant motor and nonmotor behaviors in PD.NEW & NOTEWORTHYWith the use of a large database, this study establishes that neighboring homotypic striatal spiny projection neurons have a 50% chance to form one-way collateral inhibitory connection, a substantially higher rate than previous estimates. This study also shows that dopamine denervation may alter presynaptic dopamine receptor function such that dopaminergic treatment of Parkinson's disease can weaken the surround inhibition and may reduce the contrast of the striatal outputs, potentially contributing to dopamine's profound motor and nonmotor behavioral effects.
authors.affiliation: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee.
authors.forename: Shengyuan
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee fzhou3@uthsc.edu.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000008:administration & dosage / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid; D004298:Dopamine
keywords: Parkinson's disease; basal ganglia; dopamine receptor supersensitivity; homotypic preference; l-3 4-dihydroxyphenylalanine; medium spiny neuron; surround inhibition