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Science 316 (5828): 1212-1216

Copyright © 2007 by the American Association for the Advancement of Science

Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity

Paul Berghuis,1* Ann M. Rajnicek,2* Yury M. Morozov,3* Ruth A. Ross,2 Jan Mulder,4 Gabriella M. Urbán,5 Krisztina Monory,6 Giovanni Marsicano,6{dagger} Michela Matteoli,7 Alison Canty,4 Andrew J. Irving,8 István Katona,5 Yuchio Yanagawa,9 Pasko Rakic,3 Beat Lutz,6 Ken Mackie,10{ddagger} Tibor Harkany1§

Abstract: The roles of endocannabinoid signaling during central nervous system development are unknown. We report that CB1 cannabinoid receptors (CB1Rs) are enriched in the axonal growth cones of {gamma}-aminobutyric acid–containing (GABAergic) interneurons in the rodent cortex during late gestation. Endocannabinoids trigger CB1R internalization and elimination from filopodia and induce chemorepulsion and collapse of axonal growth cones of these GABAergic interneurons by activating RhoA. Similarly, endocannabinoids diminish the galvanotropism of Xenopus laevis spinal neurons. These findings, together with the impaired target selection of cortical GABAergic interneurons lacking CB1Rs, identify endocannabinoids as axon guidance cues and demonstrate that endocannabinoid signaling regulates synaptogenesis and target selection in vivo.

1 Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
2 School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen Scotland AB25 2ZD, UK.
3 Department of Neurobiology, Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
4 Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden.
5 Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary.
6 Department of Physiological Chemistry, Johannes Gutenberg University Mainz, D-55099 Mainz, Germany.
7 Department of Medical Pharmacology and Consiglio Nazionale della Richerche Institute of Neuroscience, University of Milan, I-20129 Milan, Italy.
8 Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY, UK.
9 Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Maebashi 371-8511, Japan.
10 Departments of Anesthesiology Physiology, and Biophysics, University of Washington, Seattle, WA 98195-6540, USA.

* These authors contributed equally to this work.

{dagger} Present address: U 862 Centre de Recherche François Magendie, INSERM, Equipe AVENIR 8 Université Bordeaux 2, 146 rue Léo Saignat, F-33077 Bordeaux, France.

{ddagger} Present address: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA.

§ To whom correspondence should be addressed. E-mail: Tibor.Harkany{at}

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