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Molecular & Cellular Proteomics 7:2293-2310, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Brief Alteration of NMDA or GABA_A Receptor-mediated Neurotransmission Has Long Term Effects on the Developing Cerebral Cortex ^*,S

Angela M. Kaindl^,,¶,||, Andrea Koppelstaetter, Grit Nebrich, Janine Stuwe, Marco Sifringer^**, Claus Zabel, Joachim Klose and Chrysanthy Ikonomidou^**

From the Department of Pediatric Neurology and Institute of Human Genetics, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany, ^¶ INSERM U676 and Faculté de Médecine Denis Diderot, IFR02 and IFR25, Université Paris 7, 75019 Paris, France, and ^** Department of Pediatric Neurology, University Children's Hospital, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany

Neurotransmitter signaling is essential for physiologic brain development. Sedative and anticonvulsant agents that reduce neuronal excitability via antagonism at N-methyl-D-aspartate receptors (NMDARs) and/or agonism at -aminobutyric acid subtype A receptors (GABA_ARs) are applied frequently in obstetric and pediatric medicine. We demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABA_AR agonist phenobarbital not only has acute but also long term effects on the cerebral cortex. Changes of the cerebral cortex proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6 suggest that a suppression of synaptic neurotransmission during brain development dysregulates proteins associated with apoptosis, oxidative stress, inflammation, cell proliferation, and neuronal circuit formation. These effects appear to be age-dependent as most protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Previously performed histological evaluations of the brains revealed widespread apoptosis and decreased cell proliferation following such a drug treatment in infancy and are thus consistent with brain protein changes reported in this study. Our results point toward several pathways modulated by a reduction of neuronal excitability that might interfere with critical developmental events and thus affirm concerns about the impact of NMDAR- and/or GABA_AR-modulating drugs on human brain development.

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