Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue

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Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue Grazyna Rajkowska1,* and Craig A. Stockmeier1,2 1 2

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA Abstract: The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders.

Keywords: Glia, fronto-limbic, depression, glutamate, postmortem. WHAT IS MAJOR DEPRESSIVE DISORDER? Major depressive disorder (MDD) (also known as clinical depression or unipolar depression) is a chronic, recurrent and debilitating mental illness that affects the lives of millions of people worldwide. Depression is the 3rd leading contributor to the global burden of disease with the prevalence of depression among adults in the United States at 6.7 percent [1, 2]. MDD is characterized by core symptoms such as depressed mood, loss of interest or pleasure, changes in weight, changes in sleep, fatigue or loss of energy, feeling of worthlessness, concentration difficulties and thoughts of death or suicide [3]. Although the neurobiology of MDD has been intensely studied for several decades, its underlying etiopathology is still not fully understood and only about half of individuals with depression respond to currently available treatments [4, 5]. Cellular and molecular abnormalities arising from genetic and environmental factors are believed to be critical in the pathology of depression [6]. A consistent observation of cell pathology in MDD has been reductions in glial cells, and astrocytes, in particular [7]. INTRODUCTION TO ASTROCYTES Of the three kinds of glial cells (i.e., astrocytes, oligodendrocytes, microglia) of the central nervous system *Address correspondence to this author at the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State St., Box 127, Jackson, MS 39216-4505, USA; Tel: (601) 984-5995; Fax: (601) 984-5899; E-mail: [email protected] 1389-4501/13 $58.00+.00

(CNS), astrocytes or astroglia are the most numerous and versatile type of glial cells. Rather than serving as static or inert “brain glue” as formerly thought, astrocytes, outnumbering neurons by over fivefold, are now recognized as playing many active roles in the CNS [8-10]. The two major types of astrocytes, protoplasmic and fibrous, are distinguished by their morphology, biochemistry, development and location within CNS [11]. Protoplasmic astrocytes are found in the gray matter. Their numerous processes extend radially from the cell body which contains a spherical nucleus, and give rise to many smaller branches. Some of these processes contact blood vessels to form perivascular endfeet while others cover neuronal membranes. Fibrous astrocytes, in contrast to protoplasmic astrocytes, are present in the white matter. They have ovoid nuclei and fewer, longer and relatively thin processes with very few branches. Their cell bodies are often arranged in rows between the axon bundles and some of their processes reach the perinodal spaces of adjacent axons. Other processes from fibrous astrocytes contact blood vessels to also form perivascular endfeet [12]. Astrocytes are crucial to the neuronal microenvironment by regulating such things as glucose metabolism, neurotransmitter uptake (particularly glutamate), synaptic development and maturation and the blood brain barrier [13]. Studies revealing unexpected pathology in astrocytes in MDD and in rodent models of depressive-like behavior are outlined below. This pathology is unique and differs from reactive astrogliosis described in cases of brain injury, tumor or neurodegenerative disorders. © 2013 Bentham Science Publishers

2 Current Drug Targets, 2013, Vol. 14, No. 11

Rajkowska and Stockmeier

HUMAN POSTMORTEM STUDIES

astrocyte density or the area covered by GFAP-IR cell bodies and processes, so called area fraction. There was a significant decrease in the density of GFAP-IR astrocytes and GFAP area fraction in gray matter of the dorsolateral prefrontal cortex in younger depressed subjects (
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