Department of Molecular & Integrative Physiology, University of Illinois, Urbana, IL 61801, USA.
Neuropharmacology. 2010 Feb;58(2):413-22. doi: 10.1016/j.neuropharm.2009.09.011. Epub 2009 Sep 26.
Substance P (SP) is co-localized and co-released with gamma-amino butyric acid (GABA) from approximately 50% of GABAergic medium spiny neurons (MSNs) in the striatum. MSNs innervate several cellular targets including neighboring MSNs and cholinergic interneurons via collaterals. However, the functional role of SP release onto striatal interneurons is unknown. Here we examined SP-mediated actions on inhibitory synaptic transmission in cholinergic interneurons using whole-cell recordings in mouse corticostriatal slices. We found that SP selectively suppressed GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs), but not excitatory post-synaptic currents (EPSCs) in cholinergic interneurons. In contrast, SP did not alter IPSCs in fast-spiking interneurons and MSNs. SP suppressed IPSC amplitude in a concentration-dependent and reversible manner, and the NK1 receptor antagonist RP67580 attenuated the SP-mediated suppression. In addition, RP67580 alone enhanced the evoked IPSC amplitude in cholinergic interneurons, suggesting an endogenous action of SP on regulation of inhibitory synaptic transmission. SP did not alter the paired-pulse ratio, but reduced the amplitudes of GABA(A) agonist muscimol-induced outward currents and miniature IPSCs in cholinergic interneurons, suggesting SP exerts its effects primarily at the post-synaptic site. Our results indicate that the physiological effects of SP are to enhance the activity of striatal cholinergic interneurons and provide a rationale for designing potential new antiparkinsonian agents.
P 物质（SP）与γ-氨基丁酸（GABA）共同定位于约 50%的纹状体中间神经元（MSNs）中，并共同释放。MSNs 通过侧支神经支配包括相邻 MSNs 和胆碱能中间神经元在内的多个细胞靶标。然而，SP 释放到纹状体中间神经元上的功能作用尚不清楚。在这里，我们使用小鼠皮质纹状体切片中的全细胞膜片钳记录技术，研究了 SP 对胆碱能中间神经元抑制性突触传递的介导作用。我们发现 SP 选择性地抑制了 GABA（A）受体介导的抑制性突触后电流（IPSCs），但不影响胆碱能中间神经元的兴奋性突触后电流（EPSCs）。相比之下，SP 并未改变快速放电中间神经元和 MSNs 的 IPSCs。SP 以浓度依赖和可逆的方式抑制 IPSC 幅度，而 NK1 受体拮抗剂 RP67580 减弱了 SP 介导的抑制作用。此外，RP67580 本身增强了胆碱能中间神经元中诱发的 IPSC 幅度，表明 SP 对抑制性突触传递的调节具有内源性作用。SP 不会改变成对脉冲比，但会降低 GABA（A）激动剂 muscimol 诱导的外向电流和胆碱能中间神经元中小型 IPSC 的幅度，表明 SP 主要在突触后部位发挥作用。我们的研究结果表明，SP 的生理作用是增强纹状体胆碱能中间神经元的活性，并为设计潜在的新型抗帕金森病药物提供了依据。
