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The Journal of Neuroscience, April 2, 2008, 28(14):3546-3554; doi:10.1523/JNEUROSCI.4006-07.2008

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Neurobiology of Disease
Lasting Syndrome of Depression Produced by Reduction in Serotonin Uptake during Postnatal Development: Evidence from Sleep, Stress, and Behavior

Daniela Popa,^1,2 * Clément Léna,^3 * Chloé Alexandre,^1,2 and Joëlle Adrien^1,2

¹Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S677, F-75013 Paris, France, ²Institut National de la Santé et de la Recherche Médicale U677, Neuropsychopharmacologie, F-75013 Paris, France, and ³Unité Mixte de Recherche 8544, École Normale Supérieure, F-75005 Paris, France

Correspondence should be addressed to either of the following: Dr. Daniela Popa, Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Rutgers State University, Newark Campus, 197 University Avenue, Newark, NJ 07102, Email: popa{at}ext.jussieu.fr; or Dr. Joëlle Adrien, Inserm U677, Faculté de Médecine Pitié-Salpêtrière, 90 Boulevard de l'Hospital, 75013 Paris, France, Email: adrien{at}ext.jussieu.fr

Dysfunction of the serotonin system is implicated in sleep and emotional disorders. To test whether these impairments could arise during development, we studied the impact of early-life, transient versus genetic, permanent alterations of serotonin reuptake on sleep–wakefulness patterns, depression-related behavior, and associated physiological features. Here, we show that female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback. This syndrome was not reproduced by treatment in naive adults but resembled the phenotype of mutant mice lacking the serotonin transporter, except that these exhibited decreased serotonin autoreceptor sensitivity and additional anxiety-like behavior. Thus, alteration of serotonin reuptake during development, whether induced by external or genetic factors, causes a depressive syndrome lasting into adulthood. Such early-life impairments might predispose individuals to sleep and/or mood disorders.

Key words: 5-HT transporter; REM sleep; development; 5-HT1A autoreceptors; corticosterone; depression; anxiety; stress; knock-out mice

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Received Feb. 10, 2007; revised Feb. 15, 2008; accepted Feb. 18, 2008.

Correspondence should be addressed to either of the following: Dr. Daniela Popa, Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Rutgers State University, Newark Campus, 197 University Avenue, Newark, NJ 07102, Email: popa{at}ext.jussieu.fr; or Dr. Joëlle Adrien, Inserm U677, Faculté de Médecine Pitié-Salpêtrière, 90 Boulevard de l'Hospital, 75013 Paris, France, Email: adrien{at}ext.jussieu.fr

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