Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion.
Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion.
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DOI：
10.1111/ejn.13715
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Goldberg JA
中科院分区：
文献类型：
--
作者：
Aceves Buendia JJ;Tiroshi L;Chiu WH;Goldberg JA
帕金森病的病理生理学起源于纹状体棘神经元(DSPN)直接通路的激活不足，这一观点得到了最近在实验性帕金森病中从束旁核(PFN)到dSPN的谷氨酸能投射减弱的支持。然而，如果不考虑丘脑纹状体投射重塑对胆碱能中间神经元(CHI)的影响，就不能充分认识到它的影响，CHI本身优先激活间接通路棘神经元(ISPN)。为了研究这种丘脑纹状体投射，我们用6-羟基多巴胺(6-OHDA)去多巴胺(6-OHDA)将Cre依赖的通道视紫红质-2(ChR2)基因通过病毒途径转染到Vlec2-Cre小鼠的PFN中。同时，我们研究了在Thy1启动子下表达ChR2的6-OHDA处理转基因小鼠的皮质纹状体向CHI的投射。我们发现，6-OHDA损伤并不影响突触的短期可塑性，也不影响在这两种投射中以光遗传方式诱发的单一反应的大小。然而，我们发现6-OHDA降低了PFN突触的NMDA/AMPA比率--这一比率明显大于皮质突触的NMDA/AMPA比率--从而损害了PFN突触与CHI的突触整合。最后，我们发现在CHI上应用D5多巴胺受体激动剂可增强NMDA电流，而不影响AMPA电流或PFN突触的短期可塑性。我们认为，多巴胺耗竭导致PFN到CHI突触的NMDA电流有效去增强，从而降低突触整合。这种PFN突触上NMDA电流的选择性重塑可能对抗帕金森病中PFN突触向DSPN的选择性减弱。
The widely held view that the pathophysiology of Parkinson's disease arises from an under‐activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre‐dependent channelrhodopsin‐2 (ChR2) the PfN of Vglut2‐Cre mice that were dopamine‐depleted with 6‐hydroxydopamine (6‐OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6‐OHDA‐treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6‐OHDA lesions failed to affect short‐term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA‐to‐AMPA ratios at PfN synapses—that were significantly larger than NMDA‐to‐AMPA ratios at cortical synapses—were reduced by 6‐OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short‐term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de‐potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.
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影响因子：
16.2
作者：
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