Humans have difficulty correcting their developmental course following damage to the Central Nervous System (CNS), such as in Fetal Alcohol Spectrum Disorders (FASD). Individuals with FASD have attention deficits, poor memory, altered facial characteristics and an increased chance of behavioral problems. In FASD, ethanol has a deleterious effect on the developing brain in utero; thus, research is needed to determine the mechanisms behind FASD in order to create a treatment. We hypothesize that the inability of the CNS to correct the developmental course or repair damage following prenatal ethanol exposure is due to factors that prevent plasticity, which is vital to proper development. Some factors that we predict influence the amount of plasticity after injury are Chondroitin Sulfate Proteoglycans (CSPGs), which inhibit plasticity, and sulfatases, which inhibit CSPGs and thereby increase plasticity. Sulfatases inhibit CSPGs by degrading the inhibitory side chain, comprised of Sulfated Glycosaminoglycans (sGAGs). Degradation of these side chains deactivates the CSPGs, preventing their inhibitory effects on plasticity. One such sulfatase that degrades CSPGs is N-acetyl-galactosamine-6-sulfate sulfatase (GALNS), which in turn is inhibited by ethanol. The result of this pathway is that ethanol inhibits plasticity, which is a potential mechanism behind FASD. In FASD, developmental lack of plasticity following damage caused by ethanol exposure could contribute to many of the symptoms seen, such as learning, memory and behavioral deficits. The research proposed in this set of experiments is designed to elucidate the relationship between prenatal ethanol and plasticity, specifically by exploring astrocyte-expressed sulfatases and Chondroitin Sulfates, and their effects on neurons. To do this, we will expose astrocytes, the cells that express CSPGs and GALNS, to ethanol and/or siRNA GALNS, to knock down GALNS expression, and/or recombinant human (rh) GALNS, to increase GALNS activity. Following this, we will culture the exposed astrocytes with neurons, in order to quantify the effects of ethanol and GALNS expression on plasticity. Lastly, we will treat rats with ethanol in vivo from postnatal days 4-9, which corresponds with the human third trimester of gestation, in order to confirm the in vitro results with in vivo experiments. We expect that ethanol and siRNA GALNS treatments will decrease GALNS activity and plasticity, and increase sGAGs levels. We also predict that rhGALNS will rescue these effects. The total of these experiments will define the relationship between the Chondroitin Sulfates and sulfatases expressed by astrocytes, how ethanol and gene expression changes affect them, and the resulting effects these changes have on plasticity. In turn, this will provide a basis for future experiments examining ethanol related damage to the brain, as well as how the brain responds to altered plasticity. The results of this research have many clinical applications, as any information on why the human CNS limits plasticity will be useful in developing a treatment for individuals with FASD and possibly other plasticity related injuries.
Fetal ethanol exposure is damaging to proper development and the health of the brain. This project proposes to examine the neurobiological and molecular mechanisms behind this damage. The results of these experiments will provide a basis for understanding the short and long term effects of ethanol induced alterations in brain development.
| Goeke, C M; Roberts, M L; Hashimoto, J G et al. (2018) Neonatal Ethanol and Choline Treatments Alter the Morphology of Developing Rat Hippocampal Pyramidal Neurons in Opposite Directions. Neuroscience 374:13-24 |
| Wilhelm, Clare J; Hashimoto, Joel G; Roberts, Melissa L et al. (2018) Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain. Neuropharmacology 138:193-209 |
