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: 7782142
• 负责人: Gianmaria MACCAFERRI
• 金额: $ 28.77万
• 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/7782142
• 关键词: Affect; Anatomy; Animals; Astrocytes; Biology; Brain region; CXCR4 Receptors; 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）：癫痫可能涉及自我维持的病理循环。事实上，临床上已知癫痫发作的发生使得将来可能发生额外的癫痫发作。然而，基本的生物学并没有得到很好的理解。本申请提出研究网络信号传导的特定机制，其可能涉及某些形式的难治性癫痫的自我维持回路。我们的工作假设是基于这样一个事实，即癫痫发作往往会损害相关的大脑区域，如海马，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CXCR 4受体在海马Cajal-Retzius细胞中大量表达。我们将研究Cajal-Retzius细胞和GABA能中间神经元之间的突触相互作用，以及SDF-1如何影响它们的网络动力学。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，GABA能中间神经元的癫痫样同步被认为产生兴奋性GABAA受体介导的信号传导，这可能导致发作间期-发作转换并促进癫痫发作。因此，新的癫痫发作将产生，并且额外的反应性神经胶质增生将维持甚至增加SDF-1的可用水平，重新启动病理循环。确定GABA能网络中引发/维持癫痫样活动的假定回路的分子和细胞细节对于为预防和/或控制某些形式的难治性癫痫的不同治疗策略的发展提供新的见解是重要的。我们计划使用体外电生理学和解剖学的组合应用于从基因工程动物（CXCR 4-EGFP转基因小鼠）获得的切片。 公共卫生相关性：本申请的目的是确定新的神经元机制，有助于癫痫发作的海马体，这是一个大脑区域的一个特定的微电路，具有低阈值癫痫发作。更详细地说，该提议涉及体外癫痫样活动，其由兴奋性GABA能输入维持，并且类似于在一些对常规疗法无反应的癫痫患者中发生的动态模式。这些癫痫患者需要手术切除癫痫病灶：因此了解其疾病背后的细胞细节对于提供新的医学治疗策略至关重要。.