Department of Physiology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL, 60611-3008, USA.
Institute for Neuroanatomy, University/University Hospital Hamburg, Martinistr. 52, 20246, Hamburg, Germany.
J Physiol. 2018 Aug;596(16):3739-3758. doi: 10.1113/JP275685. Epub 2018 Jun 24.
By taking advantage of calcium imaging and electrophysiology, we provide direct pharmacological evidence for the functional expression of TRPV1 channels in hippocampal Cajal-Retzius cells. Application of the TRPV1 activator capsaicin powerfully enhances spontaneous synaptic transmission in the hippocampal layers that are innervated by the axons of Cajal-Retzius cells. Capsaicin-triggered calcium responses and membrane currents in Cajal-Retzius cells, as well as layer-specific modulation of spontaneous synaptic transmission, are absent when the drug is applied to slices prepared from TRPV1 / animals. We discuss the implications of the functional expression of TRPV1 channels in Cajal-Retzius cells and of the observed TRPV1-dependent layer-specific modulation of synaptic transmission for physiological and pathological network processing.
The vanilloid receptor TRPV1 forms complex polymodal channels that are expressed by sensory neurons and play a critical role in nociception. Their distribution pattern and functions in cortical circuits are, however, much less understood. Although TRPV1 reporter mice have suggested that, in the hippocampus, TRPV1 is predominantly expressed by Cajal-Retzius cells (CRs), direct functional evidence is missing. As CRs powerfully excite GABAergic interneurons of the molecular layers, TRPV1 could play important roles in the regulation of layer-specific processing. Here, we have taken advantage of calcium imaging with the genetically encoded indicator GCaMP6s and patch-clamp techniques to study the responses of hippocampal CRs to the activation of TRPV1 by capsaicin, and have compared the effect of TRPV1 stimulation on synaptic transmission in layers innervated or non-innervated by CRs. Capsaicin induced both calcium responses and membrane currents in ∼50% of the cell tested. Neither increases of intracellular calcium nor whole-cell currents were observed in the presence of the TRPV1 antagonists capsazepine/Ruthenium Red or in slices prepared from TRPV1 knockout mice. We also report a powerful TRPV1-dependent enhancement of spontaneous synaptic transmission onto interneurons with dendritic trees confined to the layers innervated by CRs. In conclusion, our work establishes that functional TRPV1 is expressed by a significant fraction of CRs and we propose that TRPV1 activity may regulate layer-specific synaptic transmission in the hippocampus. Lastly, as CR density decreases during postnatal development, we also propose that functional TRPV1 receptors may be related to mechanisms involved in CR progressive reduction by calcium-dependent toxicity/apoptosis.
通过钙成像和电生理学，我们提供了 TRPV1 通道在海马 Cajal-Retzius 细胞中功能表达的直接药理学证据。TRPV1 激动剂辣椒素的应用有力地增强了 Cajal-Retzius 细胞轴突支配的海马层中的自发突触传递。当药物应用于从 TRPV1 敲除小鼠制备的切片时，Cajal-Retzius 细胞中的辣椒素触发的钙反应和膜电流以及层特异性的自发突触传递调制均不存在。我们讨论了 TRPV1 通道在 Cajal-Retzius 细胞中的功能表达以及观察到的 TRPV1 依赖性层特异性突触传递调制对生理和病理网络处理的影响。
香草素受体 TRPV1 形成复杂的多模态通道，由感觉神经元表达，在痛觉中起关键作用。然而，它们在皮质回路中的分布模式和功能了解甚少。尽管 TRPV1 报告小鼠表明，在海马体中，TRPV1 主要由 Cajal-Retzius 细胞 (CRs) 表达，但缺乏直接的功能证据。由于 CRs 强烈兴奋分子层中的 GABA 能中间神经元，TRPV1 可能在层特异性处理的调节中发挥重要作用。在这里，我们利用基因编码指示剂 GCaMP6s 的钙成像和膜片钳技术研究了辣椒素激活 TRPV1 对海马 CR 反应的影响，并比较了 TRPV1 刺激对 CR 支配或非支配层中突触传递的影响。辣椒素在约 50%的测试细胞中诱导钙反应和膜电流。在存在 TRPV1 拮抗剂辣椒碱/钌红或从 TRPV1 敲除小鼠制备的切片中，均未观察到细胞内钙增加或全细胞电流。我们还报告了一种强大的 TRPV1 依赖性增强，可增强局限于 CR 支配层的中间神经元树突的自发突触传递。总之，我们的工作确立了功能性 TRPV1 由相当一部分 CR 表达，我们提出 TRPV1 活性可能调节海马中的层特异性突触传递。最后，由于 CR 密度在出生后发育过程中降低，我们还提出功能性 TRPV1 受体可能与涉及 CR 渐进减少的机制有关，这些机制与钙依赖性毒性/细胞凋亡有关。
