Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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}ki.se


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Miswiring the brain: {Delta}9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway.
G. Tortoriello, C. V. Morris, A. Alpar, J. Fuzik, S. L. Shirran, D. Calvigioni, E. Keimpema, C. H. Botting, K. Reinecke, T. Herdegen, et al. (2014)
EMBO J. 33, 668-685
   Abstract »    Full Text »    PDF »
Fetal cannabinoid receptors and the "dis-joint-ed" brain.
L. Cristino and V. Di Marzo (2014)
EMBO J. 33, 665-667
   Abstract »    Full Text »    PDF »
CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex.
J. Diaz-Alonso, T. Aguado, A. de Salas-Quiroga, Z. Ortega, M. Guzman, and I. Galve-Roperh (2014)
Cereb Cortex
   Abstract »    Full Text »    PDF »
CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release.
K. Malenczyk, M. Jazurek, E. Keimpema, C. Silvestri, J. Janikiewicz, K. Mackie, V. Di Marzo, M. J. Redowicz, T. Harkany, and A. Dobrzyn (2013)
J. Biol. Chem. 288, 32685-32699
   Abstract »    Full Text »    PDF »
Adenosine Receptor Antagonists Including Caffeine Alter Fetal Brain Development in Mice.
C. G. Silva, C. Metin, W. Fazeli, N. J. Machado, S. Darmopil, P.-S. Launay, A. Ghestem, M.-P. Nesa, E. Bassot, E. Szabo, et al. (2013)
Science Translational Medicine 5, 197ra104
   Abstract »    Full Text »    PDF »
Diacylglycerol Lipase{alpha} (DAGL{alpha}) and DAGL{beta} Cooperatively Regulate the Production of 2-Arachidonoyl Glycerol in Autaptic Hippocampal Neurons.
T. Jain, J. Wager-Miller, K. Mackie, and A. Straiker (2013)
Mol. Pharmacol. 84, 296-302
   Abstract »    Full Text »    PDF »
GABAergic Terminals Are a Source of Galanin to Modulate Cholinergic Neuron Development in the Neonatal Forebrain.
E. Keimpema, K. Zheng, S. S. Barde, P. Berghuis, M. B. Dobszay, R. Schnell, J. Mulder, P. G. M. Luiten, Z. D. Xu, J. Runesson, et al. (2013)
Cereb Cortex
   Abstract »    Full Text »    PDF »
Anandamide-CB1 Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic, and Memory Deficits.
S. Subbanna, M. Shivakumar, D. Psychoyos, S. Xie, and B. S. Basavarajappa (2013)
J. Neurosci. 33, 6350-6366
   Abstract »    Full Text »    PDF »
Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons.
E. Keimpema, G. Tortoriello, A. Alpar, S. Capsoni, I. Arisi, D. Calvigioni, S. S.-J. Hu, A. Cattaneo, P. Doherty, K. Mackie, et al. (2013)
PNAS 110, 1935-1940
   Abstract »    Full Text »    PDF »
Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development.
J. Diaz-Alonso, M. Guzman, and I. Galve-Roperh (2012)
Phil Trans R Soc B 367, 3229-3241
   Abstract »    Full Text »    PDF »
The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling.
M. Reisenberg, P. K. Singh, G. Williams, and P. Doherty (2012)
Phil Trans R Soc B 367, 3264-3275
   Abstract »    Full Text »    PDF »
The CB1 Cannabinoid Receptor Drives Corticospinal Motor Neuron Differentiation through the Ctip2/Satb2 Transcriptional Regulation Axis.
J. Diaz-Alonso, T. Aguado, C.-S. Wu, J. Palazuelos, C. Hofmann, P. Garcez, F. Guillemot, H.-C. Lu, B. Lutz, M. Guzman, et al. (2012)
J. Neurosci. 32, 16651-16665
   Abstract »    Full Text »    PDF »
Endocannabinoid-dependent plasticity at spinal nociceptor synapses.
A. Kato, P. Punnakkal, A. J. Pernia-Andrade, C. von Schoultz, S. Sharopov, R. Nyilas, I. Katona, and H. U. Zeilhofer (2012)
J. Physiol. 590, 4717-4733
   Abstract »    Full Text »    PDF »
Sticking out of the crowd: the molecular identity and development of cholecystokinin-containing basket cells.
E. Keimpema, A. Straiker, K. Mackie, T. Harkany, and J. Hjerling-Leffler (2012)
J. Physiol. 590, 703-714
   Abstract »    Full Text »    PDF »
The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives.
E. M. Marco and G. Laviola (2012)
J Psychopharmacol 26, 150-163
   Abstract »    Full Text »    PDF »
State-Dependent, Bidirectional Modulation of Neural Network Activity by Endocannabinoids.
R. Piet, A. Garenne, F. Farrugia, G. Le Masson, G. Marsicano, P. Chavis, and O. J. Manzoni (2011)
J. Neurosci. 31, 16591-16596
   Abstract »    Full Text »    PDF »
Calcium Signaling in Neuronal Development.
S. S. Rosenberg and N. C. Spitzer (2011)
Cold Spring Harb Perspect Biol 3, a004259
   Abstract »    Full Text »    PDF »
Alterations of Endocannabinoid Signaling, Synaptic Plasticity, Learning, and Memory in Monoacylglycerol Lipase Knock-out Mice.
B. Pan, W. Wang, P. Zhong, J. L. Blankman, B. F. Cravatt, and Q.-s. Liu (2011)
J. Neurosci. 31, 13420-13430
   Abstract »    Full Text »    PDF »
Recruitment of Prefrontal Cortical Endocannabinoid Signaling by Glucocorticoids Contributes to Termination of the Stress Response.
M. N. Hill, R. J. McLaughlin, B. Pan, M. L. Fitzgerald, C. J. Roberts, T. T.- Y. Lee, I. N. Karatsoreos, K. Mackie, V. Viau, V. M. Pickel, et al. (2011)
J. Neurosci. 31, 10506-10515
   Abstract »    Full Text »    PDF »
Diacylglycerol Lipase-{alpha} and -{beta} Control Neurite Outgrowth in Neuro-2a Cells through Distinct Molecular Mechanisms.
K.-M. Jung, G. Astarita, D. Thongkham, and D. Piomelli (2011)
Mol. Pharmacol. 80, 60-67
   Abstract »    Full Text »    PDF »
Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic {beta}-Cells.
W. Kim, M. E. Doyle, Z. Liu, Q. Lao, Y.-K. Shin, O. D. Carlson, H. S. Kim, S. Thomas, J. K. Napora, E. K. Lee, et al. (2011)
Diabetes 60, 1198-1209
   Abstract »    Full Text »    PDF »
Presynaptic CB1 Receptors Regulate Synaptic Plasticity at Cerebellar Parallel Fiber Synapses.
M. R. Carey, M. H. Myoga, K. R. McDaniels, G. Marsicano, B. Lutz, K. Mackie, and W. G. Regehr (2011)
J Neurophysiol 105, 958-963
   Abstract »    Full Text »    PDF »
Concerted Action of CB1 Cannabinoid Receptor and Deleted in Colorectal Cancer in Axon Guidance.
A. Argaw, G. Duff, N. Zabouri, B. Cecyre, N. Chaine, H. Cherif, N. Tea, B. Lutz, M. Ptito, and J.-F. Bouchard (2011)
J. Neurosci. 31, 1489-1499
   Abstract »    Full Text »    PDF »
DAG Lipase Involvement in Depolarization-Induced Suppression of Inhibition: Does Endocannabinoid Biosynthesis Always Meet the Demand?.
R. Min, V. Di Marzo, and H. D. Mansvelder (2010)
Neuroscientist 16, 608-613
   Abstract »    PDF »
Differential Subcellular Recruitment of Monoacylglycerol Lipase Generates Spatial Specificity of 2-Arachidonoyl Glycerol Signaling during Axonal Pathfinding.
E. Keimpema, K. Barabas, Y. M. Morozov, G. Tortoriello, M. Torii, G. Cameron, Y. Yanagawa, M. Watanabe, K. Mackie, and T. Harkany (2010)
J. Neurosci. 30, 13992-14007
   Abstract »    Full Text »    PDF »
TRPV1 acts as a synaptic protein and regulates vesicle recycling.
C. Goswami, N. Rademacher, K.-H. Smalla, V. Kalscheuer, H.-H. Ropers, E. D. Gundelfinger, and T. Hucho (2010)
J. Cell Sci. 123, 2045-2057
   Abstract »    Full Text »    PDF »
Wiring the Brain: The Biology of Neuronal Guidance.
A. Chedotal and L. J. Richards (2010)
Cold Spring Harb Perspect Biol 2, a001917
   Abstract »    Full Text »    PDF »
Alterations in the Hippocampal Endocannabinoid System in Diet-Induced Obese Mice.
F. Massa, G. Mancini, H. Schmidt, F. Steindel, K. Mackie, C. Angioni, S. H. R. Oliet, G. Geisslinger, and B. Lutz (2010)
J. Neurosci. 30, 6273-6281
   Abstract »    Full Text »    PDF »
Development of Cannabinoid 1 Receptor Protein and Messenger RNA in Monkey Dorsolateral Prefrontal Cortex.
S. M. Eggan, Y. Mizoguchi, S. R. Stoyak, and D. A. Lewis (2010)
Cereb Cortex 20, 1164-1174
   Abstract »    Full Text »    PDF »
Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice.
Y. Gao, D. V. Vasilyev, M. B. Goncalves, F. V. Howell, C. Hobbs, M. Reisenberg, R. Shen, M.-Y. Zhang, B. W. Strassle, P. Lu, et al. (2010)
J. Neurosci. 30, 2017-2024
   Abstract »    Full Text »    PDF »
Electrical dimensions in cell science.
C. D. McCaig, B. Song, and A. M. Rajnicek (2009)
J. Cell Sci. 122, 4267-4276
   Abstract »    Full Text »    PDF »
Origin, Early Commitment, Migratory Routes, and Destination of Cannabinoid Type 1 Receptor-Containing Interneurons.
Y. M. Morozov, M. Torii, and P. Rakic (2009)
Cereb Cortex 19, i78-i89
   Abstract »    Full Text »    PDF »
Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT1 Angiotensin and Other Gq/11 Protein-coupled Receptors.
G. Turu, P. Varnai, P. Gyombolai, L. Szidonya, L. Offertaler, G. Bagdy, G. Kunos, and L. Hunyady (2009)
J. Biol. Chem. 284, 16914-16921
   Abstract »    Full Text »    PDF »
Endocannabinoid-Mediated Control of Synaptic Transmission.
M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe (2009)
Physiol Rev 89, 309-380
   Abstract »    Full Text »    PDF »
The Endocannabinoid System: An Osteopathic Perspective.
J. M. McPartland (2008)
J Am Osteopath Assoc 108, 586-600
   Abstract »    Full Text »    PDF »
Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning.
J. Mulder, T. Aguado, E. Keimpema, K. Barabas, C. J. Ballester Rosado, L. Nguyen, K. Monory, G. Marsicano, V. Di Marzo, Y. L. Hurd, et al. (2008)
PNAS 105, 8760-8765
   Abstract »    Full Text »    PDF »
Regulation of excitability and plasticity by endocannabinoids and PKA in developing hippocampus.
H. Yasuda, Y. Huang, and T. Tsumoto (2008)
PNAS 105, 3106-3111
   Abstract »    Full Text »    PDF »
The Neonatal Ventromedial Hypothalamus Transcriptome Reveals Novel Markers with Spatially Distinct Patterning.
D. M. Kurrasch, C. C. Cheung, F. Y. Lee, P. V. Tran, K. Hata, and H. A. Ingraham (2007)
J. Neurosci. 27, 13624-13634
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882