Erbb4 deletion from fast spiking interneurons causes schizophrenia-like phenotypes

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.We thank D. Baeza and M. Fernandez-Otero for excellent technical assistance, A. Casillas, T. Gil, and M. Perez for general laboratory support, G. Fishell (New York University), K. Lloyd (University College Dublin), and N. Kessaris (University College London) for RCE, Erbb4, and Lhx6-Cre mouse strains, respectively, and J-M. Fritschy (University of Zurich) for GABA receptor antibodies. We are also grateful to members of the Borrell, Mann, and Rico laboratories for stimulating discussions and ideas. Supported by grants from the Spanish Government to B.R. (SAF2010-21723 and CONSOLIDER CSD2007-00023), O.M. (CSD2007-00023), M.D. (SAF2010-16427), and S.C. (CSD2007-00023, BFU2009-09938 and PIM2010ERN-00679, part of the ERANET NEURON TRANSALC project), from Fundacion Alicia Koplowitz to B.R., from the Lilly Research Awards Program to B.R. and O.M., and from Fundacio la Marato to O.M., B.R., and M.D. B.R. is an EMBO Young Investigator.Del Pino, I.; Garcia-Frigola, C.; Dehorter, N.; Brotons-Mas, JR.; Alvarez-Salvado, E.; Martinez De Lagran, M.; Ciceri, G.... (2013). Erbb4 deletion from fast spiking interneurons causes schizophrenia-like phenotypes. Neuron. 79(6):1152-1168. doi:10.1016/j.neuron.2013.07.0101152116879