Untersuchungen zur Bedeutung des Schizophrenie-assoziierten Genes ErbB4 während der Entwicklung cortikaler Mikroschaltkreise und der Funktion glutamaerger Synapsen

精神分裂症相关基因ErbB4在皮质微电路发育和谷氨酸突触功能中的重要性研究

• 批准号: 170328727
• 负责人: Dr. Sandra Ahrens
• 金额: --
• 依托单位: Cold Spring Harbor Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/170328727?language=en
• 关键词: Untersuchungen; zur; Bedeutung; des; Schizophrenie

The human Neuregulin1 gene and its receptor ErbB4 have been identified as susceptibility genes for schizophrenia, but the exact role that they play in the pathophysiology of schizophrenia is still unclear. In this research program, I propose to examine the role of ErbB4 in controlling glutamatergic synapses in specific classes of GABAergic interneurons in the prefrontal cortex. Previous studies indicate that ErbB4 controls glutamatergic synapse development and plasticity, and regulates both AMPAR and NMDAR synaptic function in excitatory neurons. The central hypothesis is that ErbB4 controls glutamatergic synapse development and plasticity in cortical inhibitory interneurons. ErbB4 deficiency early in life leads to NMDAR hypofunction and impedes the recruitment of GABAergic interneurons into cortical microcircuits. Conceivably, that could result in cortical circuit dysfunction and aberrant behavior later in life that are similar to those brought about by psychotomimetic NMDAR blockade or by direct NMDAR deficiency. By determining the role of ErbB4 in the glutamatergic synapse of GABAergic interneurons and dissecting its role in regulating the development and function of PFC microcircuits, we will gain insight into the genetic causes of NMDAR hypofunction and the resulting synaptic and circuit changes that potentially contribute to the pathophysiology of schizophrenia.A number of complementary methodologies will be used, including electrophysiology, two-photon imaging, and molecular genetics. The specific aims are to determine:1. The mechanism by which ErbB4 controls glutamatergic synapse maturation and function in cortical GABAergic interneurons.2. The role of ErbB4 in PFC microcircuit development and normal cognitive function.3. Whether the effects of ErbB4 deficiency in PFC are mediated by glutamatergic hypofunction.

人类Neuregulin1基因及其受体ErbB4已被确定为精神分裂症的易感基因，但它们在精神分裂症病理生理学中所起的确切作用仍不清楚。在这个研究项目中，我建议研究 ErbB4 在控制前额皮质特定类别 GABA 能中间神经元中谷氨酸能突触中的作用。先前的研究表明，ErbB4 控制谷氨酸能突触的发育和可塑性，并调节兴奋性神经元中的 AMPAR 和 NMDAR 突触功能。中心假设是 ErbB4 控制皮质抑制性中间神经元的谷氨酸突触发育和可塑性。生命早期的 ErbB4 缺乏会导致 NMDAR 功能减退，并阻碍 GABA 能中间神经元招募到皮质微电路中。可以想象，这可能会导致以后生活中的皮质回路功能障碍和异常行为，类似于拟心理 NMDAR 阻断或直接 NMDAR 缺乏所带来的后果。通过确定 ErbB4 在 GABA 能中间神经元的谷氨酸突触中的作用，并剖析其在调节 PFC 微电路的发育和功能中的作用，我们将深入了解 NMDAR 功能减退的遗传原因以及由此产生的突触和电路变化，这些变化可能导致精神分裂症的病理生理学。将使用许多补充方法，包括 电生理学、双光子成像和分子遗传学。具体目标是确定： 1． ErbB4控制皮质GABA能中间神经元谷氨酸突触成熟和功能的机制。2． ErbB4在PFC微电路发育和正常认知功能中的作用。 3． ErbB4 缺乏对 PFC 的影响是否是由谷氨酸能功能减退介导的。