Human Post-Mortem Pathology (in-situ Hyb etc.)

人类死后病理学（原位杂交等）

• 批准号: 7478381
• 负责人: GRAZYNA RAJKOWSKA
• 金额: $ 24.18万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478381
• 关键词: 3-Dimensional; Antidepressive Agents; Astrocytes; Autopsy; Axon; Cell Count; Cells; Complex; D Cells; Depressed mood; Etiology; Functional disorder; Glutamates; Homeostasis; Human; Immunohistochemistry; In Situ; In Situ Hybridization; Interneurons; Lead; Life; Localized; Major Depressive Disorder; Mental Depression; Messenger RNA; Neuroglia; Neurons; Numbers; Pathology; Prefrontal Cortex; Presynaptic Receptors; Proteins; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; System; Techniques; Testing; Tissue Sample; age related; calbindin; cell type; density; depressive symptoms; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; nerve supply; neuroimaging; neurotoxic; novel; postsynaptic; prevent; receptor; serotonin receptor; serotonin transporter; size

Major depressive disorder (MDD) is characterized by reductions in the density and size of neuronal and glial cells in prefrontal cortex. We find these cellular changes to be age-dependent as younger depressed show prominent reductions in the density of glial cells (astrocytes), whereas older depressed have marked reductions in the density of pyramidal (presumably glutamate) neurons and calbindin-immunoreactive interneurons (mostly co-localizing GABA). Since, astrocytes regulate concentration of glutamate, an excess of which is neurotoxic, we propose that an early deficit in astrocytes in MDD could lead to an increase in the extracellular concentration of glutamate and to a reduction in pyramidal and GABA neurons later in life. Hence, there may be imbalances in GABA/glutamate homeostasis that are consistent with neuroimaging studies revealing changes in levels of GABA and glutamate in MDD which are reversible with antidepressant (SSRI) treatment. Cortical neurons are regulated in complex ways by serotonin acting (at least) at serotonin- 1A and -2A receptors located on these neurons and astrocytes. Pathology in ascending serotoninergic axons and postsynaptic receptors may be related to the activity, number and size of glutamate and/or GABA neurons and astrocytes in MDD. To date, there have been no studies on the expression or localization of serotonin receptors on specific cortical cell types in depression. The overall hypothesis is that in depression there will be age-dependent reductions in the density of astrocytes, glutamate pyramidal neurons and GABA interneurons, and that the expression of regulatory serotonin-1A and -2A receptors on these cells will be altered. These cell reductions will also be correlated with an age-related loss of serotonin innervation in prefrontal layers. To test these hypotheses, we will directly identify and quantify the packing density of astrocytes and glutamate and GABA neurons expressing mRNA for specific proteins (Aim 1). Moreover, we will assess the integrity of the serotonin system regulators (postsynaptic receptors and presynaptic axons) of prefrontal cells by estimating the proportion of cell types expressing mRNA for serotonin-1 A and -2A receptors (Aim 2), and the density of serotonin axons expressing the serotonin transporter (Aim 3). Double in situ hybridization, immunohistochemistry and 3-D cell counting techniques will be used in the same postmortem tissue sampled from the prefrontal cortex of younger and older subjects with MDD and non-depressed controls as used in our cell counting studies. This project will identify the cellular substrates of glutamate, GABA and serotonin interactions in the cortex and their potential role in the etiology, pathophysiology and age-related progression of depression. It may also reveal novel targets for preventing depressive illness and better antidepressant drug treatment.

重度抑郁症（MDD）的特征是神经元和神经胶质细胞的密度和大小减少