|dc.description.abstracteng||Neuregulin 1 (NRG1) is the best characterized member of a family of epidermal growth factor (EGF)-like domain containing proteins that serve as ligands for tyrosine kinase receptors of the ErbB family. NRG1 and its main receptor in the brain, ErbB4, have been involved in neural development, neurotransmission and synaptic plasticity. Additionally, NRG1 isoform-specific expression patterns in the brain have been described, but isoform-specific functions remain unclear. Nrg1 is a robustly associated schizophrenia susceptibility gene in many populations. Examination of blood cells and post mortem brain tissue revealed that increased Nrg1 expression occurs in schizophrenia patients, including a notable increase in Ig-Nrg1 mRNA. Together with ErbB4 hyperphosphorylation observed in post mortem brains of schizophrenia patients, this suggests that NRG1/ErbB4 hyperstimulation could represent a component of schizophrenia etiology. However, the underlying pathomechanisms are unknown.
In the present study, we investigated brain endophenotypes associated with cortical-restricted Ig-NRG1/ErbB4 hyperstimulation. For this purpose, a conditional transgenic mouse line was produced that permits stage- and cell type-specific overexpression of the Ig-NRG1 isoform under control of the β-actin promoter after Cre-mediated removal of a “floxed” STOP-cassette. A comprehensive analysis of this mouse model revealed that physiologically relevant Ig-NRG1 overexpression in glutamatergic projection neurons resulted in chronic ErbB4 hyperphosphorylation in the neocortex and hippocampus. ErbB4 hyperstimulation was associated with impaired hippocampal -oscillation and altered social behavior. Biochemical analyses revealed a preferential activation of the AKT pathway upon Ig-NRG1 overexpression. Furthermore, moderate projection neuron-specific overexpression of Ig-NRG1 allowed us to investigate the subcellular localization of the protein, which appeared to be associated with the potassium channel Kv2.1 in the somatodendritic compartment. These results provide a first insight into possible molecular pathomechanisms and schizophrenia-relevant endophenotypes induced by Ig-NRG1-mediated ErbB4 hyperstimulation in cortical networks.
In a second project, NRG1 signaling functions in ErbB4-expressing GABAergic interneurons have been investigated in conditional NRG1 mutants. Cre-mediated elimination of NRG1 from parvalbumin-positive (Parv+) interneurons resulted in body weight reduction, a shivering phenotype, increased motor activity, and a reduced number of interneurons in cortical layers II-III. Thus, in contrast to projection neuron-specific loss- or (moderate) overexpression of NRG1, these findings suggest that NRG1-mediated autocrine signaling in Parv+ interneurons serves an essential role in the regulation of inhibitory circuit functions.
Finally, in a pilot project a new mouse line for the conditional overexpression of NRG2, a closely related ErbB4 ligand in the brain, has been generated by homologous recombination into the Rosa26 locus of embryonic stem cells.||de