Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Neurosci. 2010 Aug;13(8):958-66. doi: 10.1038/nn.2592. Epub 2010 Jul 4.
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.
纹状体 D2 型多巴胺受体（D2Rs）与神经精神疾病的病理生理学有关，包括帕金森病和精神分裂症。尽管这些受体调节纹状体突触可塑性，但多巴胺能调节谷氨酸能突触的机制尚不清楚。我们结合光遗传学、双光子显微镜和谷氨酸光解技术，研究了 D2R 对小鼠纹状体苍白球神经元谷氨酸能突触传递的依赖调节作用。我们发现，D2R 激活可减少皮质纹状体谷氨酸释放，并使突触和动作电位诱发的 Ca2+流入树突棘分别减少约 50%。Ca2+信号的调节是通过蛋白激酶 A（PKA）依赖性调节 NMDA 型谷氨酸受体的 Ca2+内流介导的，该调节受 D2R 抑制和 2A 型腺苷受体（A2ARs）激活增强。D2R 还通过 R 型电压门控 Ca2+通道产生 PKA 和 A2AR 独立的 Ca2+内流减少。这些发现表明，多巴胺通过多种途径调节棘突 Ca2+，而 PKA 的竞争调节控制纹状体中 NMDA 受体介导的 Ca2+信号。
