Zhang Yuchun, Deng Ping, Ruan Yiwen, Xu Zao C
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, Indianapolis, IN 46202, USA.
Stroke. 2008 Aug;39(8):2370-6. doi: 10.1161/STROKEAHA.107.506824. Epub 2008 Jun 5.
Spiny neurons in the neostriatum are highly vulnerable to ischemia. Despite an enormous body of research suggesting that dopamine is involved in ischemia-induced neuronal loss in the striatum, it remains unclear how dopamine interacts with the glutamatergic excitotoxicity that is widely accepted as a major cause of ischemic cell death. Our study was designed to investigate the effects of dopamine D1 receptor (D1R) activation on excitatory neurotransmission in postischemic striatal neurons.
We used the 4-vessel occlusion ischemia model and brain slice preparations. Whole-cell voltage-clamp recording was performed on striatal neurons to measure excitatory postsynaptic currents (EPSCs). Systemic administration of a D1R agonist after ischemia and hematoxylin/eosin staining were performed to evaluate the effects of D1R activation on ischemia-induced neuronal degeneration in the striatum.
D1R activation depressed EPSCs in postischemic striatal neurons. The depression was attributable to inhibition of presynaptic release. An activator of cAMP-dependent protein kinase A (PKA) mimicked the depressive effects of D1R activation. Bath application of a PKA inhibitor blocked the depression of EPSCs, whereas intracellular postsynaptic application of the PKA inhibitor had no effect. The D1R agonist failed to reduce EPSC amplitude in the presence of an adenosine A1 receptor antagonist. Systemic administration of a D1R agonist after ischemia significantly attenuated ischemia-induced cell death in the striatum.
These results indicate that D1R activation presynaptically depresses excitatory synaptic transmission in striatal neurons after ischemia through activation of PKA and adenosine A1 receptors and thus demonstrate a novel mechanism of D1R-mediated protection against ischemia.
新纹状体中的棘状神经元对缺血高度敏感。尽管大量研究表明多巴胺参与纹状体缺血诱导的神经元损失，但多巴胺如何与被广泛认为是缺血性细胞死亡主要原因的谷氨酸能兴奋性毒性相互作用仍不清楚。我们的研究旨在探讨多巴胺D1受体（D1R）激活对缺血后纹状体神经元兴奋性神经传递的影响。
我们使用四血管闭塞缺血模型和脑片制备。对纹状体神经元进行全细胞电压钳记录以测量兴奋性突触后电流（EPSC）。缺血后全身给予D1R激动剂并进行苏木精/伊红染色，以评估D1R激活对纹状体缺血诱导的神经元变性的影响。
D1R激活使缺血后纹状体神经元的EPSC降低。这种降低归因于对突触前释放的抑制。环磷酸腺苷依赖性蛋白激酶A（PKA）的激活剂模拟了D1R激活的抑制作用。浴用PKA抑制剂可阻断EPSC的降低，而细胞内突触后应用PKA抑制剂则无作用。在存在腺苷A1受体拮抗剂的情况下，D1R激动剂未能降低EPSC幅度。缺血后全身给予D1R激动剂可显著减轻纹状体缺血诱导的细胞死亡。
这些结果表明，D1R激活通过激活PKA和腺苷A1受体在突触前抑制缺血后纹状体神经元的兴奋性突触传递，从而证明了D1R介导的抗缺血保护的新机制。
