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The Journal of Neuroscience, July 11, 2007, 27(28):7532-7540; doi:10.1523/JNEUROSCI.5330-06.2007

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Behavioral/Systems/Cognitive
Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

Claire-Marie Rangon,^1,2 * Silvia Fortes,^3 * Vincent Lelièvre,^1,2 Philippe Leroux,⁴ Frank Plaisant,^1,2 Chantal Joubert,³ Laurence Lanfumey,⁵ Charles Cohen-Salmon,³  and Pierre Gressens^1,2,6 

¹Inserm, Unité 676, 75019 Paris, France, ²Université Paris 7, Faculté de Médecine Denis Diderot, Institut Fédératif de Recherche 02 (IFR02), 75005 Paris, France, ³Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7593, Faculté de Médecine Pitié-Salpétrière, 75634 Paris, France, ⁴Inserm, Avenir, IFR02, Faculté de Médecine et de Pharmacie, 76183 Rouen, France, ⁵Inserm, Unité 677, 75013 Paris, France, and ⁶Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019 Paris, France

Address correspondence to Dr. Pierre Gressens, Inserm, Unité 676, Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France. Email: gressens{at}rdebre.inserm.fr

Cerebral palsy remains a public health priority. Recognition of factors of susceptibility to perinatal brain lesions is key for the prevention of cerebral palsy. In most cases, the pathophysiology of these lesions is thought to involve prior exposure to predisposing factors that make the developing brain more vulnerable to perinatal events. The present study tested the hypothesis that exposure to chronic minimal stress throughout gestation would sensitize the offspring to neonatal excitotoxic brain lesions, which mimic lesions observed in cerebral palsy. Pregnant mice were exposed to chronic, ultramild stress, applied throughout gestation. Neonatal brain lesions were induced by intracerebral injection of glutamate analogs. Excitotoxic lesions were significantly worsened in pups exposed to gestational stress. Stress induced a significant rise of circulating corticosterone levels both in pregnant mothers and in newborn pups. The deleterious effects of stress on excitotoxicity were totally suppressed in mice with reduced levels of glucocorticoid receptors. Stress induced a significant increase of neopallial NMDA binding sites in the offspring. At adulthood, animals exposed to stress and neonatal excitotoxic challenge showed a significant impairment in the Morris water maze test when compared with animals exposed to the excitotoxic challenge but not the gestational stress. These findings suggest that stress during gestation, which may mimic low-level stress in human pregnancy, could be a novel risk factor for cerebral palsy.

Key words: cerebral palsy; neonatal; excitotoxicity; glucocorticoids; NMDA; sensitization

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Received Dec. 11, 2006; revised June 5, 2007; accepted June 5, 2007.

Address correspondence to Dr. Pierre Gressens, Inserm, Unité 676, Hôpital Robert Debré, 48 Boulevard Serurier, 75019 Paris, France. Email: gressens{at}rdebre.inserm.fr

This article has been cited by other articles:

				A. Desfeux, F. El Ghazi, S. Jegou, H. Legros, S. Marret, V. Laudenbach, and B. J. Gonzalez Dual Effect of Glutamate on GABAergic Interneuron Survival during Cerebral Cortex Development in Mice Neonates Cereb Cortex, September 16, 2009; (2009) bhp181v1. [Abstract] [Full Text] [PDF]

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