title: Dopamine D2 receptors regulate collateral inhibition between striatal medium spiny neurons.
abstract: The principle neurons of the striatum are GABAergic medium spiny neurons (MSNs), whose collateral synapses onto neighboring neurons play critical roles in striatal function. MSNs can be divided by dopamine receptor expression into D1-class and D2-class MSNs, and alterations in D2 MSNs are associated with various pathological states. Despite overwhelming evidence for D2 receptors (D2Rs) in maintaining proper striatal function, it remains unclear how MSN collaterals are specifically altered by D2R activation. Here, we report that chronic D2R stimulation regulates MSN collaterals in vitro by presynaptic and postsynaptic mechanisms. We used corticostriatal cultures from mice in which MSN subtypes were distinguished by fluorophore expression. Quinpirole, an agonist for D2/3 receptors, was used to chronically activate D2Rs. Quinpirole increased the rate and strength of collateral formation onto D2R-containing MSNs as measured by dual whole-cell patch-clamp recordings. Additionally, these neurons were more sensitive to low concentrations of GABA and exhibited an increase in gephyrin puncta density, suggesting increased postsynaptic GABAA receptors. Last, quinpirole treatment increased presynaptic GABA release sites, as shown by increased frequency of sIPSCs and mIPSCs, correlating with increased VGAT (vesicular GABA transporter) puncta. Combined with the observation that there were no detectable differences in sensitivity to specific GABAA receptor modulators, we provide evidence that D2R activation powerfully transforms MSN collaterals via coordinated presynaptic and postsynaptic alterations. As the D2 class of MSNs is highly implicated in Parkinson's disease and other neurological disorders, our findings may contribute to understanding and treating the changes that occur in these pathological states.
authors.affiliation: Graduate Program in Physiology and Biophysics, Department of Pharmacology & Physiology, Georgetown University, Washington, DC 20007, USA. rrl23@georgetown.edu
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Lalchandani
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: van der Goes
authors.forename: John G
authors.initials: JG
authors.lastname: Partridge
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D018491:Dopamine Agonists; D008565:Membrane Proteins; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C073441:gephyrin; C493406:vesicular GABA transporter; D019257:Quinpirole; D005680:gamma-Aminobutyric Acid