Abstract
Postmortem studies reveal structural and molecular alterations of astrocytes and oligodendrocytes in both the gray and white matter (GM and WM) of the prefrontal cortex (PFC) in human subjects with chronic alcohol abuse or dependence. These glial cellular changes appear to parallel and may largely explain structural and functional alterations detected using neuroimaging techniques in subjects with alcohol use disorders (AUDs). Moreover, due to the crucial roles of astrocytes and oligodendrocytes in neurotransmission and signal conduction, these cells are very likely major players in the molecular mechanisms underpinning alcoholism-related connectivity disturbances between the PFC and relevant interconnecting brain regions. The glia-mediated etiology of alcohol-related brain damage is likely multifactorial since metabolic, hormonal, hepatic and hemodynamic factors as well as direct actions of ethanol or its metabolites have the potential to disrupt distinct aspects of glial neurobiology. Studies in animal models of alcoholism and postmortem human brains have identified astrocyte markers altered in response to significant exposures to ethanol or during alcohol withdrawal, such as gap-junction proteins, glutamate transporters or enzymes related to glutamate and gamma-aminobutyric acid (GABA) metabolism. Changes in these proteins and their regulatory pathways would not only cause GM neuronal dysfunction, but also disturbances in the ability of WM axons to convey impulses. In addition, alcoholism alters the expression of astrocyte and myelin proteins and of oligodendrocyte transcription factors important for the maintenance and plasticity of myelin sheaths in WM and GM. These changes are concomitant with epigenetic DNA and histone modifications as well as alterations in regulatory microRNAs (miRNAs) that likely cause profound disturbances of gene expression and protein translation. Knowledge is also available about interactions between astrocytes and oligodendrocytes not only at the Nodes of Ranvier (NR), but also in gap junction-based astrocyte-oligodendrocyte contacts and other forms of cell-to-cell communication now understood to be critical for the maintenance and formation of myelin. Close interactions between astrocytes and oligodendrocytes also suggest that therapies for alcoholism based on a specific glial cell type pathology will require a better understanding of molecular interactions between different cell types, as well as considering the possibility of using combined molecular approaches for more effective therapies.
Highlights
Alcohol use disorder (AUD) is defined in the webpage of the National Institute of Alcohol Abuse and Alcoholism as a chronic relapsing brain disease involving compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using
Since neurons are the main conveyors of information between brain regions, much attention has been placed on the role of neuronal pathology in the various disorders caused by AUDs in human subjects and experimental animals (Abrahao et al, 2017)
Prominent among the critical roles of astrocytes are the exchange with blood vessels of energy-rich metabolites to support neuronal metabolism, the buffering of extracellular ions exchanged during synaptic neurotransmission/propagation of action potentials, the reuptake of synaptically-released glutamate and gammaaminobutyric acid (GABA), the recycling of these and other transmitters for reutilization or metabolism, the release of small molecular cofactors, such as serine or glycine required for activation of the N-methyl-D-aspartate-type (NMDAtype) glutamate receptors, the release of gliotransmitters or cytokine-like molecules to communicate with other neural cells, and the expression of immune-like activities within the nervous system (Cali et al, 2008)
Summary
Alcohol use disorder (AUD) is defined in the webpage of the National Institute of Alcohol Abuse and Alcoholism as a chronic relapsing brain disease involving compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using This disorder results in severe behavioral, neurological and other medical pathologies that eventually depend on disturbances of cellular function and metabolism (Abrahao et al, 2017). It is well known that a large proportion of alcoholics, despite serious behavioral and emotional pathology, show only minor or inconspicuous neurological deficits of the kind mentioned above, and these subjects are dubbed as ‘‘uncomplicated’’ alcoholics In these subjects, AUDs do not necessarily result in catastrophic or global loss of brain tissue of neuronal or glial cell numbers (Jensen and Pakkenberg, 1993). Uncomplicated subjects are not entirely free of neuropathological alterations at the cellular level either because they show regionally selective degeneration of pyramidal neurons or their dendrites in some brain regions such as the PFC (Kril et al, 1997)
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