Ethanol exerts profound effects on the developing brain, which range from structural abnormalities to functional anomalies, resulting in compromised cognitive and behavioral functions characteristic of fetal alcohol spectrum disorders (FASD). Neuronal maturation is an essential process in the development of the nervous system. Brain-specific chondroitin sulfate proteoglycans (CSPGs) neurocan and brevican constitute inhibitory cues that prevent the extension of neurites in improper directions therefore contributing to the proper formation of neuronal architecture. Neurocan and brevican inhibit neurite outgrowth and are highly produced by glial cells, and astrocytes in particular, both in vitro and in vivo. CSPG are glycoproteins consisting of core-proteins attached to linear chains of glycosaminoglycans (GAGs) called chondroitin sulfates (CS), which consists in chondroitin-4 sulfate (C4S) and chondroitin-6 sulfate (C6S);the inhibitory properties of CSPGs depend on their core-protein and their GAG chains. Several enzymes are involved in the biosynthesis and degradation of GAG chains;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. An unscheduled increase in CSPGs in the still developing brain may lead to altered brain connectivity and to premature decrease in neuronal plasticity. In this proposal we hypothesize that ethanol-treated astrocytes inhibits neuritogenesis by increasing CSPGs. More specifically, we hypothesize that ethanol, through the inhibition of ARSB and GALNS activity in astrocytes, increases CS-GAG and CSPG core-protein neurocan and brevican levels in these cells leading to the inhibition of hippocampal neuron neuritogenesis.
Specific aim 1 will investigate the effect of ethanol on ARSB and GALNS activity and expression, on CS-GAG, neurocan, and brevican levels, and on the role of ARSB and GALNS in modulating ethanol-induced inhibition of astrocyte-mediated hippocampal neuritogenesis in vitro.
Specific Aim 2 will investigate the effect of in vivo neonatal alcohol exposure on ARSB and GALNS activity and protein and mRNA expression, CS-GAG, C4S-GAG, and neurocan- and brevican-bound sGAG levels, and neurocan and brevican protein and mRNA expression in the hippocampus.
Ethanol exerts profound effects on the developing brain resulting in compromised cognitive and behavioral functions characteristic of fetal alcohol spectrum disorders (FASD). This proposal is extremely innovative as it investigates for the first time the modulation of a class of glycoproteins, chondroitin sulfate proteoglycans, by ethanol and their role in ethanol-induced inhibition of neuronal plasticity. These studies will introduce te field of glycobiology/sulfatase enzyme biology to FASD research and will identify novel ethanol targets toward which design new and appropriate interventions for FASD.
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