Cajal-Retzius Cells and Neuronal Signaling in Postnatal Cortical Networks

描述(申请人提供)：癫痫可能涉及自持性病理循环。事实上，临床上已经知道，癫痫的发生可能会在未来发生更多的癫痫发作。然而，其潜在的生物学原理还没有被很好地理解。这项申请建议研究网络信号的特定机制，这些机制可能涉及某些形式的顽固性癫痫背后的自我维持环路。我们的工作假设是基于这样一个事实，即癫痫发作经常损害相关的大脑区域，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受体在海马区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细胞的激活可能是GABA能网络癫痫样活动的触发因素。在一些对药物治疗无效的患者中，GABA能中间神经元的癫痫样同步化被认为产生了兴奋性的GAAA受体介导的信号，这可能导致发作间期转换和促进癫痫发作。因此，将产生新的癫痫发作，而额外的反应性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。明确GABA能网络中启动/维持癫痫样活动的可能回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的结合应用于从基因工程动物(CXCR4-EGFP转基因小鼠)获得的切片。 公共卫生相关性：这项应用的目的是在海马体的特定微电路中识别有助于癫痫发生的新的神经机制，海马体是一个癫痫发作阈值较低的大脑区域。更详细地说，这项建议涉及由兴奋性GABA能输入维持的体外癫痫样活动，类似于一些对传统治疗无效的癫痫患者的动态模式。这些癫痫患者需要手术切除癫痫灶：因此，了解他们疾病背后的细胞细节对于为医学治疗提供新的策略是必不可少的。。

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. .