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The Journal of Neuroscience, January 17, 2007, 27(3):684-691; doi:10.1523/JNEUROSCI.4595-06.2007

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Behavioral/Systems/Cognitive
Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice

C. L. Wellman,¹ A. Izquierdo,² J. E. Garrett,¹ K. P. Martin,¹ J. Carroll,³ R. Millstein,² K.-P. Lesch,⁴ D. L. Murphy,³ and A. Holmes²

¹Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, ²Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, Maryland 20852, ³Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, and ⁴Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Würzberg 97080, Germany

Correspondence should be addressed to A. Holmes at the above address. Email: holmesan{at}mail.nih.gov

A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear- and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear- and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.

Key words: serotonin transporter; gene; stress; prefrontal cortex; amygdala; extinction

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Received Oct. 23, 2006; revised Nov. 28, 2006; accepted Dec. 11, 2006.

Correspondence should be addressed to A. Holmes at the above address. Email: holmesan{at}mail.nih.gov

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