title: Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors.
abstract: Striatal D2-type dopamine receptors (D2Rs) have been implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson's disease and schizophrenia. Although these receptors regulate striatal synaptic plasticity, the mechanisms underlying dopaminergic modulation of glutamatergic synapses are unclear. We combined optogenetics, two-photon microscopy and glutamate uncaging to examine D2R-dependent modulation of glutamatergic synaptic transmission in mouse striatopallidal neurons. We found that D2R activation reduces corticostriatal glutamate release and attenuates both synaptic- and action potential-evoked Ca2+ influx into dendritic spines by approximately 50%. Modulation of Ca2+ signaling was mediated by a protein kinase A (PKA)-dependent regulation of Ca2+ entry through NMDA-type glutamate receptors that was inhibited by D2Rs and enhanced by activation of 2A-type adenosine receptors (A2ARs). D2Rs also produced a PKA- and A2AR-independent reduction in Ca2+ influx through R-type voltage-gated Ca2+ channels. These findings reveal that dopamine regulates spine Ca2+ by multiple pathways and that competitive modulation of PKA controls NMDAR-mediated Ca2+ signaling in the striatum.
authors.affiliation: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higley
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Sabatini
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium