Cortical network dysfunctions in response to hyperstimulated Neuregulin/ErbB4 signaling
Final Report Abstract
The EGF-like ligand NRG1 and its receptor tyrosine kinase ErbB4 represent a paradigmatic signaling module with diverse functions in the central and peripheral nervous system. Human NRG1 and ErbB4 gene variants as genetic risk factors in schizophrenia, but the underlying pathomechanisms are largely unknown. A comparative analysis of loss- and gain-of-function NRG1 mouse mutants showed that chronically altered NRG1/ErbB4 signaling in the brain causes synaptic, morphological and behavioral endophenotypes with relevance for schizophrenia. Moreover, an investigation of conditional gain-of-function transgenic mouse models identified several endophenotypes, including impaired g-oscillation, ventricular enlargement, and locomotor hyperactivity, as isoform-specific consequences of hyperactivated NRG1 signaling in glutamatergic networks. We conclude that an ‘‘optimal’’ level of NRG1 signaling is necessary to balance a variety of schizophrenia-relevant brain functions. Identified endophenotype profiles suggest that human NRG1 risk haplotypes exert a gain-of-function effect. ErbB4, the main NRG1 receptor in the brain, is expressed in parvalbumin (PV)+ interneurons and regulates various GABAergic functions. In contrast, direct ErbB4 functions in glutamatergic neurons are not well defined. We found that mouse mutants with a selective elimination of ErbB4 from postnatal glutamatergic neurons (CKnull) displayed impaired fear conditioning, altered excitatory and inhibitory neurotransmission, and enhanced short-term potentiation in the hippocampus. Moreover, we showed that the LTP defect in transgenic mice with neuronal overexpression of CRD-NRG1 is partially restored in a CKnull mutant background. Together with a preferential CRD-NRG1 expression in the soma (but not presynapse) of glutamatergic neurons, we suggest that glutamatergic network functions are modulated by autocrine NRG1/ErbB4 signaling in the somato-dendritic compartment of projection neurons. Cholinergic C-type synapses at spinal cord a-motor neurons harbor a characteristic ER- derived postsynaptic subsurface cistern (SSC) and serve as a new model system to examine NRG1 functions at CNS synapses. Our studies in NRG1 transgenic mice suggest that CRD- NRG1 may act as an SSC organizer, whereas Ig-NRG1 could promote synaptogenesis of presynaptic cholinergic terminals. Our data also indicate that a-motor neuron-derived NRG1 signals regulate the activity of microglial cells in the spinal cord. Taken together, we concluded that distinct NRG1 isoform-mediated signaling functions regulate the matching between preand postsynaptic C-bouton elements in a-motor neurons. To permit corresponding studies in GABAergic neurons, we produced a mouse line for Credependent overexpression of NRG2 (Stop-Nrg2) by targeting the ROSA locus via homologous recombination in embryonic stem cells. Breeding of Stop-Nrg2 mice to a PV-Cre driver line confirmed transgenic NRG2 expression in PV+ neurons. Thus, Stop-Nrg2 mice provide the first in vivo-model to investigate hyperstimulated NRG2 signaling in GABAergic interneurons.
Publications
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(2014). Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. Cell Rep. 8,1130-1145
Agarwal A., Zhang M., Trembak-Duff I., Unterbarnscheidt T., Radyushkin K., Dibaj P., Martins de Souza D., Boretius S., Brzózka M.M., Steffens H., Berning S., Teng Z., Gummert M., Tantra M., Guest P.C., Willig K.I., Frahm J., Hell S.W., Bahn S., Rossner M.J., Nave K.A., Ehrenreich H., Zhang W., Schwab M.H.
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(2016). Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions. Proc Natl Acad Sci. 113, E479-87
Lee Y., Li Y., Mikesh M., Smith I., Nave K.A., Schwab M.H., Thompson W.J.
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(2016). OSO paradigm-A rapid behavioral screening method for acute psychosocial stress reactivity in mice. Neurosci. 314, 1-11
Brzózka M.M., Unterbarnscheidt T., Schwab M.H., Rossner M.J.
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(2017). Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Mol Med. 9, 1448-1462
Wehr M.C., Hinrichs W., Brzózka M.M., Unterbarnscheidt T., Herholt A., Wintgens J.P., Soto- Bernardini M.C., Kravchenko M., Nave K.A., Wichert S.P., Falkai P., Zhang W., Schwab M.H., Rossner M.J.
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(2018). Altered hippocampal gene expression and structure in transgenic mice over-expressing neuregulin 1 (NRG1) type I. Transl Psychiatry 8, 229
Deakin I. H., Godlewska B. R., Walker M. A., Huang G.-J., Schwab M.H., Nave K. A., Law A. J., Harrison P. J.
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(2019). A Neuregulin-1 type I signaling axis mediates Schwann cell interactions upstream of disease hallmarks in the most common inherited demyelinating neuropathy. Nature Commun. 10,1467
Fledrich R., Akkermann D., Abdelaal T.A., Schuetza V., Hermes D., Schäffner E., Soto-Bernadini M.C., Götze T., Klink A., Kusch K., Krüger M., Moebius W., Brück W., Mueller W.C., Sereda M.W., Schwab M.H., Nave K.A., Stassart R.M.
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(2019). Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair. FASEB J. 33, 7833-7851
Salvany S., Casanovas A., Tarabal O., Piedrafita L., Hernández S., Santafé M., Soto- Bernardini M.C., Calderó J., Schwab M.H., Esquerda J.E.
