Neurexin Dysfunction in Adult Neurons Results in Autistic-like Behavior in Mice

Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1δC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1δC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1δC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes. © 2014 The Authors.Research at the F.G.S. lab was funded by grants from NEURON-ERANET (EUHF-AUTISM, PIM2010ERN-0070), Instituto de Salud Carlos III (PI111058), and Junta de Andalucía (P11-CVI-7599). We thank Dr. Leon Lagnado (University of Sussex) for the generous gift of the sypHy construct, Dr. Oscar Pintado for pronuclear injection, Dr. Angel Barco for helpful advice with bitransgenic mice, and Dr. Maria Luz Montesinos and Itziar Benito for assistance with some behavioral tests. Technical assistance during the generation of transgenic mice was provided by María Luisa Pecero. The authors wish to thank Drs. Rafael Fernández-Chacón and Amalia Martinez-Mir for support and critical reading of the manuscript. E.R-L received a fellowship from V Plan Propio de Investigación (Universidad de Sevilla), and J.L.N.-G is a recipient of a Juan de la Cierva MINECO contract. Part of the study was performed at CITIUS (Universidad de Sevilla).Peer Reviewe