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

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

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