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Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling

Abstract

Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component1,2. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia3,4, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (γ-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia.

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Figure 1: ErbB4 is expressed by many interneurons in the postnatal neocortex and hippocampus, but not in pyramidal cells at P30.
Figure 2: Nrg1 promotes GABAergic differentiation and synaptogenesis.
Figure 3: Nrg1 and ErbB4 signalling is necessary for inhibitory synapse formation in vivo.
Figure 4: Conditional deletion of Erbb4 disrupts excitatory input to hippocampal interneurons.

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Acknowledgements

We thank G. Fernández for technical assistance, T. Gil and A. Casillas for general laboratory support, C. Lai for antibodies and plasmids, F. H. Gage for retroviral vectors, and K. Campbell (Dlx5/6-Cre-IRES-GFP), M. Gassmann (HER4heart and Erbb4- ), S. Goebbels and K.-A. Nave (NexCre ), and G. Szabó (GAD65-GFP) for mouse strains. We are grateful to L. Menéndez de la Prida and P. Aivar for help with electrophysiological experiments, M. Maravall for critical reading of the manuscript, and members of the Borrell, Marín and Rico laboratories for stimulating discussions and ideas. This work was supported by grants from Spanish Ministry of Science and Innovation SAF2008-00770 (to O.M.), SAF2007-61904 (to B.R.), BFU2006-07138 (to J.L.), and CONSOLIDER CSD2007-00023 (to J.L., O.M. and B.R.), Consejería de Educación y Ciencia de la Junta de Comunidades de Castilla-La Mancha PAI08-0174-6967 (to R.L.), fundació la Caixa (to B.R.) and the EURYI (see http://www.esf.org/euryi) scheme award (to O.M). P.F. is the recipient of a Marie Curie Intra-European Fellowship.

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P.F., O.M. and B.R. planned the experiments, and P.F. analysed the results. A.V.P. and J.L. performed the electrophysiological experiments and analysed the results. R.L. performed the ultrastructural analysis. M.V. and R.P. carried out in utero electroporation and in utero viral injections, respectively. K.L., R.L., J.L., O.M. and B.R. provided reagents, materials and analysis tools. P.F., O.M. and B.R. discussed the results and wrote the paper.

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Correspondence to Oscar Marín or Beatriz Rico.

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Fazzari, P., Paternain, A., Valiente, M. et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464, 1376–1380 (2010). https://doi.org/10.1038/nature08928

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