Astrocytes, alcohol, and the extracellular matrix: Project P002

Diagram of neuron and P002's project

Several genome-wide studies, including studies from the previous funding period of the PARC, identified the extracellular matrix (ECM) and astrocytes as being involved in both the risk for and the effects of alcohol drinking. Cells in the brain parenchyma are separated by the extracellular space, accounting for approximately 20% of the total volume of the mature rodent brain and containing a highly organized ECM that form an insoluble network around cells. The brain interstitial ECM significantly contributes to the molecular signals regulating neuronal plasticity. Recent research has shown that astrocytes are major producers of the brain interstitial ECM as well as ECM proteases, which are involved in the remodeling of the ECM.The study of astrocyte functions in vivo has been hampered by the lack of appropriate molecular and genetic tools. Techniques developed in recent yearsallow for the discrimination between astrocytes and other brain cell types and will lead to a better mechanistic understanding of the roles of astrocytes in the brain. ECM proteins are post-translationally modified by glycosylation. Proteoglycans are major components of the brain ECM and consist of a core protein covalently bound to long, unbranched glycosaminoglycans (GAGs) formed by repeating disaccharides, modified by sulfation. Hyaluronicacid (HA), also a major component of the ECM, is a non-sulfate GAG and is not covalently bound to proteins. GAGs are involved in the modulation of neuronal plasticity. Chondroitin sulfate (CS), and in particular chondroitin-4-sulfate (C4S)-GAGs are inhibitors of neuronal plasticity. HA and heparan sulfates (HS) may, instead, promote neuronal plasticity. CS, HS, and HA are present in the brain ECM as well as in some brain-specific ECM structures such as the perineuronal nets.The overall goal of this proposal is to identify differential expression of astrocyte-specific genes (with a major emphasis on genes involved in the formation and remodeling of the ECM) and differential levels of ECM GAGs associated with alcohol drinking in three brain regions involved in addiction:the prefrontal cortex (PFC), the hippocampus, and the nucleus accumbens (NAc). Strategies to differentiate between the risk and the effects of alcohol drinking will be employed.