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

人类神经调节蛋白1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中所起的确切作用尚不清楚。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的gaba能中间神经元的谷氨酸能突触中的作用。已有研究表明，ErbB4控制着兴奋性神经元中谷氨酸能突触的发育和可塑性，并调节AMPAR和NMDAR突触功能。核心假设是ErbB4控制皮层抑制性中间神经元的谷氨酸突触发育和可塑性。生命早期ErbB4缺乏导致NMDAR功能低下，阻碍gaba能中间神经元向皮质微回路募集。可以想象，这可能导致皮层回路功能障碍和生活后期的异常行为，类似于由拟神经性NMDAR阻断或直接NMDAR缺乏所带来的后果。通过确定ErbB4在gaba能中间神经元谷氨酸能突触中的作用，并剖析其在调节PFC微回路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，以及由此导致的突触和回路改变，这些改变可能有助于精神分裂症的病理生理。一些互补的方法将被使用，包括电生理学、双光子成像和分子遗传学。具体的目的是确定：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。ErbB4在PFC微电路发育和正常认知功能中的作用。ErbB4缺乏对PFC的影响是否由谷氨酸能功能减退介导。

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.