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Published online on January 28, 2008, 10.1073/pnas.0711555105
PNAS | February 5, 2008 | vol. 105 | no. 5 | 1710-1715


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BIOLOGICAL SCIENCES / NEUROSCIENCE
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism

Stephane Jamain*,{dagger},{ddagger}, Konstantin Radyushkin§, Kurt Hammerschmidt, Sylvie Granon||, Susann Boretius**, Frederique Varoqueaux*, Nelina Ramanantsoa{dagger}{dagger}, Jorge Gallego{dagger}{dagger}, Anja Ronnenberg§, Dorina Winter§, Jens Frahm**, Julia Fischer, Thomas Bourgeron{dagger},{ddagger}{ddagger},§§, Hannelore Ehrenreich§,§§, and Nils Brose*,§§

*Abteilung Molekulare Neurobiologie and §Division für Klinische Neurowissenschaften, Max-Planck-Institut für Experimentelle Medizin, 37075 Göttingen, Germany; {dagger}Groupe Génétique Humaine et Fonction Cognitive and ||Unité de Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, 75724 Paris, France; Forschergruppe Kognitive Ethologie, Deutsches Primatenzentrum, 37077 Göttingen, Germany; **Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut für Biophysikalische Chemie, 37077 Göttingen, Germany; {dagger}{dagger}Institut National de la Santé et de la Recherche Médicale, U676, Hôpital Robert Debré, 75019 Paris, France; and {ddagger}{ddagger}Université Denis Diderot Paris 7, 75013 Paris, France

Communicated by Jean-Pierre Changeux, Institut Pasteur, Paris, France, December 7, 2007 (received for review September 28, 2007)

Autism spectrum conditions (ASCs) are heritable conditions characterized by impaired reciprocal social interactions, deficits in language acquisition, and repetitive and restricted behaviors and interests. In addition to more complex genetic susceptibilities, even mutation of a single gene can lead to ASC. Several such monogenic heritable ASC forms are caused by loss-of-function mutations in genes encoding regulators of synapse function in neurons, including NLGN4. We report that mice with a loss-of-function mutation in the murine NLGN4 ortholog Nlgn4, which encodes the synaptic cell adhesion protein Neuroligin-4, exhibit highly selective deficits in reciprocal social interactions and communication that are reminiscent of ASCs in humans. Our findings indicate that a protein network that regulates the maturation and function of synapses in the brain is at the core of a major ASC susceptibility pathway, and establish Neuroligin-4-deficient mice as genetic models for the exploration of the complex neurobiological disorders in ASCs.

behavior | neuroligin | synaptogenesis

Author contributions: S.J. and K.R. contributed equally to this work; S.J., K.R., K.H., S.G., S.B., F.V., J.G., J. Frahm, J. Fischer, T.B., H.E., and N.B. designed research; S.J., K.R., K.H., S.G., S.B., F.V., N.R., A.R., and D.W. performed research, S.J., K.R., K.H., S.G., S.B., F.V., N.R., J.G., J. Frahm, J. Fischer., T.B., H.E., and N.B. analyzed data; and S.J., K.R., S.B., J. Fischer, T.B., H.E., and N.B. wrote the paper.

{ddagger}Present address: INSERM, U 841, IMRB, Département Génétique, éq. Psychiatrie Génétique, 94010 Créteil, France.

The authors declare no conflict of interest.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (mouse Neuroligin 4 cDNA sequence, accession no. EF694290).

This article contains supporting information online at www.pnas.org/cgi/content/full/0711555105/DC1.

§§To whom correspondence may be addressed. E-mail: thomasb{at}pasteur.fr, ehrenreich{at}em.mpg.de, or brose{at}em.mpg.de

© 2008 by The National Academy of Sciences of the USA


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