Astrocytes and Alcohol Throughout the Lifespan

Abstract

Evidence for involvement of astrocytes in several neurodegenerative disorders and in drug addiction has been emerging over the last 2 decades, but only in recent years have astrocytes been investigated for their roles in alcohol use disorder (AUD). As a result, there is a need to evaluate the existing preclinical literature that supports the involvement of astrocytes in the effects of alcohol exposure. Here, we review emerging evidence about responses of astrocytes to alcohol and the contributions of astrocytes to the development of AUD. We review studies of single-cell RNA sequencing with a focus on alcohol and astrocyte heterogeneity, astrocyte reactivity, and the role of astrocytes in remodeling the extracellular matrix. Effects of alcohol on astrocyte-modulated synaptic transmission are also discussed, with an emphasis on studies that have never been reviewed before. Because astrocytes play essential roles in brain development, we review recent research on the role of astrocytes in fetal alcohol spectrum disorder (FASD), which may also shed light on fetal development of psychiatric disorders that have a high prevalence in individuals affected by FASD. Finally, this review highlights gaps in knowledge about astrocyte biology and alcohol that need further research. Particularly, there is a dire need to identify astrocyte subpopulations and molecules that are susceptible to alcohol exposure and may be targets for therapeutic intervention.

Keywords: Alcohol use disorder; Astrocytes; Ethanol; Fetal alcohol spectrum disorders; Glia; Preclinical.

Figure 1:. Sites of alcohol action on astrocytes in AUD models for which further research is needed.

Astrocyte heterogeneity within the same brain area (represented in the figure by different colors) reflects different functions of these cells in different cellular contexts. RNA-seq and scRNA-seq studies have provided valuable insights into astrocytes transcriptomic changes associated with specific astrocyte functions. Future spatial transcriptomics or multiplexed RNA in situ hybridization studies will reveal the functional consequences of changes in gene expression in specific subpopulations of astrocytes by alcohol. A: PAP morphology and molecular properties are altered by ethanol which may, in turn, alter synaptic transmission. Future studies should focus on the identification of specific molecules and molecular mechanisms involved in astrocyte-synapse interactions altered by alcohol. B: Evidence from animal and in vitro models indicates that alcohol triggers neuroimmune responses in astrocytes. A complete characterization of alcohol-induced reactive astrocytes needs to be carried out to understand adaptive and maladaptive astrocyte reactivity. C: Astrocytes produce and secrete most of the ECM proteins in the brain interstitial ECM, the ECM surrounding the nodes of Ranvier and synapses, and the ECM forming PNNs. PNNs (shown covering the neurons in the figure) are altered by chronic alcohol exposure. More studies are needed to address the role of astrocytes in ECM remodeling and their relationship to the cellular and synaptic consequences of ethanol exposure. Created in https://BioRender.com.

Figure 2:. Sites of alcohol action on astrocytes in FASD models for which further research is needed.

In the developing brain, astrogliogenesis from radial glia (A), astrocyte-mediated neuronal development (B; represented here are ECM proteins, such as laminin, fibronectin, CSPGs, and ECM proteases that are released by astrocytes and involved in dendritic arborization), and astrocyte-mediated BBB development (C) are altered by alcohol. Further investigation of astrocyte-mediated mechanisms of altered brain development should be studied by carrying out alcohol exposures during limited time-windows corresponding to specific ontogenetic processes of interest. Consequences of these exposures should be measured immediately after exposure to assess the developmental processes altered at the time of exposure as well as at a later time-point when long-term effects of these exposures are manifested. Created in https://BioRender.com. The neuron in Figure 2C is our original artwork.