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Pathology in Astroglia, Glutamate, and GABA in Major Depressive Disorder: Evidence from Studies of Human Postmortem Tissue

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Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders

Abstract

Evidence will be reviewed for pathology in astroglial cells, and for glutamate and γ-aminobutyric acid (GABA) neurons, their receptors and transporters in human postmortem brain tissue from subjects diagnosed with major depressive disorder (MDD). These observations will be compared with similar endpoints in preclinical animal models of chronic stress. Repeated stressful experiences or stressful life events can be risk factors for the onset or relapse of depressive episodes. Thus, animal studies on the behavioral and biological responses to exposure to chronic stress may shed light on underlying pathological mechanisms relevant to findings in postmortem brain tissue from subjects that experienced depression. Moreover, dysfunction of astrocytes, glutamate, and GABA—vital components of the tripartite synapse—will be proposed as a major source of fundamental pathology in depression and related animal behavioral models. Finally, the role of glutamate-based drugs in treating depressive symptoms will be discussed. In summary, evidence from postmortem brain tissue in MDD and animal models related to depression supports the hypothesis that pathology in astrocytes, glutamate, and GABA systems may be fundamental to the pathophysiology of depression.

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Abbreviations

AQP4:

Aquaporin 4

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

BDNF:

Brain derived neurotrophic factor

Ca + 2 :

Calcium

CA1:

Ammoni horn region 1

CA3:

Ammoni horn region 3

CNS:

Central nervous system

EAAT1:

Excitatory amino acid transporter-1

EAAT2:

Excitatory amino acid transporter-2

GABA:

γ-aminobutyric acid

GAD:

Glutamic acid decarboxylase

GC1:

Mitochondrial glutamate carrier

GFAP:

Glial fibrillary acidic protein

GLAST:

Glutamate–aspartate transporter

GLT1:

Glutamate transporter 1

GluR1:

AMPA receptor subunit 1

GluR2:

AMPA receptor subunit 2

GluR3:

AMPA receptor subunit 3

GluR4:

AMPA receptor subunit 4

GluR5:

Kainate receptor subunit 5

GRINA:

Glutamate receptor ionotropic NMDA-associated protein 1

IR:

Immunoreactive

MDD:

Major depressive disorder

mGluR5:

Metabotropic glutamate receptor 5

mRNA:

Messenger ribonucleic acid

mTOR:

Mammalian target of rapamycin

NeuN:

Neuronal nuclei (neuron-specific nuclear protein)

NMDA:

N-methyl-D-aspartate

NR1:

NMDA receptor 1

NR2A:

NMDA receptor 2A

NR2B:

NMDA receptor 2B

NR2C:

NMDA receptor 2C

PSD95:

Postsynaptic density protein 95

SAP102:

Synapse-associated protein 102

SSRI:

Serotonin-selective reuptake inhibitor

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Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 39216, Jackson, MS, USA

    Grazyna Rajkowska

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  1. Grazyna Rajkowska
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Correspondence to Grazyna Rajkowska .

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  1. Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy

    Maurizio Popoli

  2. Department of Psychology, University of South Florida, Tampa, Florida, USA

    David Diamond

  3. Psychiatry Depression Research Program, Yale School of Medicine, New Haven, Connecticut, USA

    Gerard Sanacora

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Rajkowska, G. (2014). Pathology in Astroglia, Glutamate, and GABA in Major Depressive Disorder: Evidence from Studies of Human Postmortem Tissue. In: Popoli, M., Diamond, D., Sanacora, G. (eds) Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1056-4_14

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