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的病理生理学中所起的确切作用尚不清楚。在这个研究项目中，我打算研究ErbB4在前额叶皮质特定类别的GABA能中间神经元中控制谷氨酸能突触的作用。以往的研究表明，ErbB4调控兴奋性神经元中谷氨酸能突触的发育和可塑性，调节AMPAR和NMDAR的突触功能。中心假设是ErbB4控制皮质抑制性中间神经元中谷氨酸能突触的发育和可塑性。早期缺乏ERBB4会导致NMDAR功能低下，并阻碍GABA能中间神经元向皮质微回路的募集。可以想象，这可能会导致大脑皮质回路功能障碍和晚年的异常行为，类似于类似精神分裂的NMDAR阻断或直接NMDAR缺乏所带来的情况。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微回路的发育和功能中的作用，我们将深入了解NMDAR功能低下的遗传原因以及由此导致的突触和回路变化，这些变化可能有助于精神分裂症的病理生理学。我们将使用一些补充方法，包括电生理学、双光子成像和分子遗传学。其具体目的是确定：1.ErbB4调控皮质GABA能神经元内谷氨酸能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低下所介导。

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.