Cajal-Retzius cells and neuronal signaling in postnatal cortical networks

项目摘要 这项竞争性续签申请的广泛目的是为了解 海马网，特别强调一个相当神秘和未被充分研究的神经细胞 类型：Cajal-Retzius细胞(CR)。 研究这些细胞的重要性被文献报道所强调，这些报告表明细胞密度增加。 颞叶癫痫患者亚群的海马区CRS，他们也 在很小的时候就经历了发热性癫痫。这一观察表明，生理过程 控制CR的数量和功能可能参与癫痫的形成过程。 这个项目的科学前提依赖于我们实验室的两个主要发现。第一, 我们已经提供了明确的证据表明，海马区CRS是谷氨酸能的第三个种群。 神经元(除锥体细胞和颗粒细胞外)，它们持续存在于成熟的海马网和 完全集成在它的微电路中。第二，我们最近发现CRS表达多态， 温度门控和钙离子渗透通道TRPV1。 这些发现为研究血管紧张素转换酶的生理和病理功能提供了独特的机会。 CRS及其驱动的微电路在转基因动物中的水平有条件地增加 TRPV1的表达或条件消融的囊泡谷氨酸转运体。 特别是，我们将测试CRS对TRPV1的功能表达决定其 在发育中的海马区的密度和/或调节它们的突触输出。最后，我们将测试 高热惊厥范围内的温度可影响海马CR依赖的假说 在体外和体内通过TRPV1的微电路。

Project Summary The broad aim of this competitive renewal application is to shed new light on the structure and functions of the hippocampal network, with a specific emphasis on a rather mysterious and understudied neuronal cell type, the Cajal-Retzius cell (CR). The significance of studying these cells is highlighted by literature reports indicating increased densities of CRs in the hippocampus of a subpopulation of patients suffering from temporal lobe epilepsy, who also experienced febrile seizures at early ages. This observation has suggested that the physiological process controlling CR numbers and functions may be involved in the epileptogenic process. The scientific premise underlying this project relies on two main discoveries made by our laboratory. First, we have provided unequivocal evidence that hippocampal CRs are a third population of glutamatergic neurons (in addition to pyramidal and granule cells), which persist in the mature hippocampal network and are fully integrated in its microcircuits. Second, we have recently found that CRs express the polymodal, temperature-gated and Ca2+ permeable channel TRPV1. These discoveries provide unique opportunities to study the physiological and pathological functions of CRs and of the microcircuits they drive in genetically-altered animals with conditionally increased levels of TRPV1 expression or conditionally ablated vesicular glutamate transporters. In particular, we will test the hypotheses that the functional expression of TRPV1 by CRs determines their densities in the developing hippocampus and/or regulates their synaptic output. Lastly, we will test the hypothesis that temperatures in the febrile seizure range can impact hippocampal CR-dependent microcircuits via TRPV1 in vitro and in vivo.