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

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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.