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PNAS 102 (26): 9388-9393

Copyright © 2005 by the National Academy of Sciences.

NEUROSCIENCE

Altering cannabinoid signaling during development disrupts neuronal activity

C. Bernard * {dagger}, M. Milh *, Y. M. Morozov *, {ddagger}, Y. Ben-Ari *, T. F. Freund {ddagger}, and H. Gozlan * {dagger}, §

*Institut de Neurobiologie de la Méditerranée–Institut National de la Santé et de la Recherche Médicale U29, 163 Route de Luminy BP13, 13273 Marseille Cédex 09, France; and {ddagger}Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 8., Szigony u. 43, H-1083, Hungary

Edited by Ricardo Miledi, University of California, Irvine, CA

Accepted for publication April 26, 2005.

Received for publication December 22, 2004.

Abstract: In adult cortical tissue, recruitment of GABAergic inhibition prevents the progression of synchronous population discharges to epileptic activity. However, at early developmental stages, GABA is excitatory and thus unable to fulfill this role. Here, we report that retrograde signaling involving endocannabinoids is responsible for the homeostatic control of synaptic transmission and the resulting network patterns in the immature hippocampus. Blockade of cannabinoid type 1 (CB1) receptor led to epileptic discharges, whereas overactivation of CB1 reduced network activity in vivo. Endocannabinoid signaling thus is able to keep population discharge patterns within a narrow physiological time window, balancing between epilepsy on one side and sparse activity on the other, which may result in impaired developmental plasticity. Disturbing this delicate balance during pregnancy in either direction, e.g., with marijuana as a CB1 agonist or with an antagonist marketed as an antiobesity drug, can have profound consequences for brain maturation even in human embryos.

Key Words: endocannabinoid • epilepsy • interneurons • neonates • drug abuse

Author contributions: C.B., H.G., T.F.F., and Y.B.-A. designed research; C.B., H.G., M.M., and Y.M.M. performed research; C.B., H.G., M.M., and Y.M.M. analyzed data; and C.B. and H.G. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: CB1, cannabinoid type 1; PSC, postsynaptic current; DSG, depolarization-induced suppression of GABA PSCs; GDP, giant depolarizing potential; SPW, sharp wave burst; PC, pyramidal cell; IN, interneuron; CCK, cholecystokinin; Pn, n-day-old.

{dagger} C.B. and H.G. contributed equally to this work.

§ To whom correspondence should be addressed. E-mail: gozlan{at}inmed.univ-mrs.fr.

© 2005 by The National Academy of Sciences of the USA

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