Cajal-Retzius Cells and Neuronal Signaling in Postnatal Cortical Networks

产后皮质网络中的 Cajal-Retzius 细胞和神经元信号传导

• 批准号: 8196943
• 负责人: Gianmaria MACCAFERRI
• 金额: $ 32.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196943
• 关键词: Affect; Anatomy; Animals; Astrocytes; Biology; Brain region; CXCR4 Receptors; CXCR4 gene; Cajal-Retzius cells; Data; Development; Electrophysiology (science); Engineering; Epilepsy; Epileptogenesis; Excision; Future; Gliosis; Hippocampus (Brain); In Vitro; Interneurons; Intractable Epilepsy; Lead; Mediating; Medical; Microglia; Molecular; Neurons; Patients; Pattern; Pharmacological Treatment; Prevention strategy; Property; Seizures; Signal Transduction; Slice; Source; Stromal Cell-Derived Factor 1; Synapses; Testing; Therapeutic; Transgenic Mice; Work; base; cell type; chemokine; conventional therapy; excitatory neuron; in vitro activity; insight; novel; postnatal; public health relevance; receptor-mediated signaling

DESCRIPTION (provided by applicant): Self-sustaining pathological loops may be involved in epilepsy. Indeed, it is clinically known that the occurrence of a seizure makes it likely that additional seizures will occur in the future. However, the underlying biology is not well understood. This application proposes to study specific mechanisms of network signaling that may be involved in a self-sustaining loop underlying some forms of intractable epilepsy. Our working hypothesis is based on the fact that seizures often damage the brain regions involved, such as the hippocampus, and induce reactive changes and proliferation of astrocytes and microglia. Both cell types are a rich source of the chemokine stromal cell-derived factor 1 (SDF-1), whose CXCR4 receptors are abundantly expressed by hippocampal Cajal-Retzius cells. We will study the synaptic interactions between Cajal-Retzius cells and GABAergic interneurons, and how their network dynamics are affected by SDF-1. Our preliminary data suggest the possibility that SDF-1-mediated activation of Cajal-Retzius cells is the trigger of epileptiform activity in GABAergic networks. Epileptiform synchronization of GABAergic interneurons in some patients unresponsive to pharmacological treatment is believed to generate excitatory GABAA receptor-mediated signaling, which may lead to interictal-ictal transitions and promote seizures. Thus, new seizures would be produced, and additional reactive gliosis would maintain or even increase the available levels of SDF-1, restarting the pathological loop. Defining the molecular and cellular details of a putative circuit initiating/maintaining epileptiform activity in GABAergic networks is important to provide new insights for the development of different therapeutic strategies for the prevention and/or control of some forms of intractable epilepsies. We plan to use a combination of in vitro electrophysiology and anatomy applied to slices obtained from genetically-engineered animals (CXCR4-EGFP transgenic mice). PUBLIC HEALTH RELEVANCE: The purpose of this application is to identify novel neuronal mechanisms that contribute to epileptogenesis in a specific microcircuit of the hippocampus, which is a brain region with a low threshold for seizures. In more detail, this proposal concerns epileptiform activity in vitro that is sustained by excitatory GABAergic input and is similar to dynamic patterns occurring in some epileptic patients who do not respond to conventional therapies. These epileptic patients require surgical removal of the epileptic focus: hence understanding the cellular details underlying their illness is imperative to provide new strategies for medical treatments. .

描述（由申请人提供）：自我维持的病理循环可能与癫痫有关。事实上，临床上已知的是，癫痫发作的发生很可能使未来发生额外的癫痫发作。然而，潜在的生物学并没有被很好地理解。这个应用程序提出了研究网络信号的具体机制，可能涉及一个自我维持的循环潜在的一些形式的难治性癫痫。我们的工作假设是基于这样一个事实，即癫痫发作通常会损害大脑相关区域，如海马体，并诱导星形胶质细胞和小胶质细胞的反应性变化和增殖。这两种细胞类型都是趋化因子基质细胞衍生因子1 （SDF-1）的丰富来源，其CXCR4受体在海马Cajal-Retzius细胞中大量表达。我们将研究Cajal-Retzius细胞与gaba能中间神经元之间的突触相互作用，以及SDF-1如何影响其网络动力学。我们的初步数据表明，sdf -1介导的Cajal-Retzius细胞激活可能是gaba能网络中癫痫样活动的触发因素。在一些对药物治疗无反应的患者中，GABAA能中间神经元的癫痫样同步被认为产生兴奋性GABAA受体介导的信号，这可能导致发作间期转变并促进癫痫发作。因此，会产生新的癫痫发作，并且额外的反应性胶质瘤会维持甚至增加可用的SDF-1水平，重新启动病理循环。确定gaba能网络中启动/维持癫痫样活动的假定电路的分子和细胞细节，对于开发预防和/或控制某些形式的难治性癫痫的不同治疗策略具有重要意义。我们计划将体外电生理学和解剖学相结合，应用于基因工程动物（CXCR4-EGFP转基因小鼠）获得的切片。