Astrocyte-neuron interactions and sulfatases in Fetal Alcohol Spectrum Disorders

  • Guizzetti, Marina, (PI)

Project: Research projectResearch Project

Description

? DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) are characterized by structural brain abnormalities and compromised cognitive and behavioral functions. Neuronal connectivity and plasticity are affected by developmental alcohol exposure. The exposure of astrocytes to ethanol inhibits neuritogenesis in hippocampal neurons co-cultured with ethanol-treated astrocytes. However, a lack of understanding of the mechanisms by which ethanol affects neuronal structural plasticity in the developing brain persists. Filling tis gap will open the path to the identification of highly effective treatments to prevent or ameliorat the developmental effects of ethanol. Lecticans are inhibitory proteoglycans that, in the brain, prevent the extension of axons and dendrites. Lecticans consist of a core-protein moiety covalently bound to linear chains of disaccharides, chondroitin sulfates glycosaminoglycans (CS-GAGs), which are comprised mostly of chondroitin-4 sulfate (C4S) and chondroitin-6 sulfate (C6S); the inhibitory properties of lecticans depend on their core-protein and their sGAG side-chains. Two sulfatase enzymes, arylsulfatase B (ARSB) and galactose-6-sulfatase (GALNS) remove sulfate groups from C4S and C6S respectively and are required for the degradation of CS-GAGs. We find that ethanol inhibits the activity of ARSB and GALNS and that ethanol and ARSB silencing increase the expression of the lectican neurocan and C4S-GAG content in astrocytes in vitro. ARSB activity is inhibited, neurocan and sGAG levels are upregulated, and pyramidal neuron dendritic arborization is reduced also in the hippocampus of neonatal rats after in vivo ethanol exposure. Reduced ARSB activity and dendritic arborization persist up to post-natal day 36 and is correlated with reduced performance in spatial learning and memory tasks. In this proposal we hypothesize that the inhibition of ARSB and GALNS activity by ethanol in the developing hippocampus induces an unscheduled increase in lectican (neurocan, brevican, and versican) core-protein and CS-GAG levels leading to decreased in neuronal structural plasticity; these effects are long-lasting and causally linked to reduced performance in
learning and memory tasks and are rescued by recombinant (r)ARSB. We plan to test our hypothesis by pursuing the following three specific aims: 1) To investigate the mechanisms of ethanol-induced sulfatase inhibition and the consequences on lectican core-proteins and sGAG levels and on CS disaccharide levels and composition in astrocytes. 2) To investigate the role of: sulfatases, SUMF1, lecticans, and oxidative stress on ethanol-treated astrocyte inhibition of neurite outgrowth. 3) To investigate the effects of in vivo neonatal ethanol exposure and of rARSB injections on sulfatase activity, lectican expression, sGAG levels and CS disaccharide levels, and dendritic arborization in the hippocampus and on spatial learning and memory. The proposed work is innovative and significant as it explores a novel mechanism underlying ethanol-induced inhibition of neuronal plasticity and will yield strategies aimed at sulfatase enzyme activation for the treatment of alcohol teratogenesis therefore advancing FASD research.
StatusActive
Effective start/end date9/5/156/30/20

Keywords

  • Medicine(all)