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      Decreased Expression of Synapse-Related Genes and Loss of Synapses in Major Depressive Disorder

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          Abstract

          Previous imaging and postmortem studies have reported a reduction in brain volume and a decrease in the size and density of neurons in the dorsolateral prefrontal cortex (dlPFC, area 9) of subjects with major depressive disorder (MDD). 1, 2 These findings suggest that synapse number and function are decreased in dlPFC of depressed patients. However, there has been no direct evidence for synapse loss in MDD and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal decreased expression of synaptic function-related genes in dlPFC of MDD subjects and a corresponding reduction in the number of synapses. We also identify a transcriptional repressor that is increased in MDD, and that when expressed in PFC neurons is sufficient to decrease expression of synapse-related genes, cause loss of spines and dendrites, and produce depressive behavior in rodent models of depression.

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          Most cited references45

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          Dendritic organization in the neurons of the visual and motor cortices of the cat.

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            Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.

            This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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              Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.

              The prefrontal cortex (PFC) plays an important role in higher cognitive processes, and in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Here we examined the effect of repeated restraint stress on dendritic spine number in the medial PFC. Rats were perfused after receiving 21 days of daily restraint stress, and intracellular iontophoretic injections of Lucifer Yellow were carried out in layer II/III pyramidal neurons in the anterior cingulate and prelimbic cortices. We found that stress results in a significant (16%) decrease in apical dendritic spine density in medial PFC pyramidal neurons, and confirmed a previous observation that total apical dendritic length is reduced by 20% in the same neurons. We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses, but may impair these neurons' capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                26 June 2012
                September 2012
                01 March 2013
                : 18
                : 9
                : 1413-1417
                Affiliations
                [1 ]Depts. of Psychiatry, New Haven, CT, USA
                [2 ]Depts. of Neurobiology, and New Haven, CT, USA
                [3 ]Depts. of OBGYN Yale University, New Haven, CT, USA
                [4 ]Dept. of Biophysics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
                [5 ]Dept. Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, MS
                [6 ]Dept. of Bioinspired Science, and Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul, Korea
                [7 ]Dept. of Biochemistry and Molecular Biology, Hanyang University College of Medicine, Seoul, Korea
                Author notes
                Correspondence: , Ronald S. Duman, Ph.D., Professor of Psychiatry and Pharmacology, Director, Abraham Ribicoff Research Facilities, Laboratory of Molecular Psychiatry, Yale University School of Medicine, 34 Park Street, room 308, New Haven, CT 06508, Phone: (203) 974-7726, Fax: (203) 974-7724, ronald.duman@ 123456yale.edu
                Article
                NIHMS388567
                10.1038/nm.2886
                3491115
                22885997
                71be84bf-8075-4f0b-9062-29564116be56

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                Categories
                Article

                Medicine
                postmortem,stress,prefrontal cortex,microarray,transcription factor,repressor
                Medicine
                postmortem, stress, prefrontal cortex, microarray, transcription factor, repressor

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