Glia-neuron Interaction in Fetal Alcohol Spectrum Disorders

Portland Va Medical Center, Portland OR

Investigators

Linked publications & trials

Abstract

Background and Innovation: Hippocampal alterations associated with deficits in hippocampal-dependent cognitive behaviors have been reported in individuals with Fetal Alcohol Spectrum Disorders (FASD). We have found that third trimester-equivalent alcohol exposure increases dendritic arborization in CA1 hippocampal neurons, which may be associated with altered brain connectivity and function. We show evidence that the expression and translation of two extracellular proteases, ADAMTS5 and tissue plasminogen activator (tPA), are upregulated in astrocytes by neonatal alcohol exposure. ADAMTS5 and tPA proteolytically cleave the extracellular matrix protein brevican, an inhibitor of neuronal development, and generate a brevican proteolytic fragment, brevikine, which increases neurite outgrowth in hippocampal neurons in culture. The overarching hypothesis of this proposal is that neonatal ethanol-induced increase in astrocyte ADAMTS5 and tPA levels is mechanistically linked to the proteolysis of brevican and the formation of brevikine and is responsible for ethanol- induced increased dendritic arborization at PD7. This sequence of events leads to altered neuronal development and gene expression and deficits in hippocampus-dependent cognitive behavior at PD30. We will also test the hypothesis that knocking out ADAMTS5 and tPA in astrocytes restores gene expression and structural plasticity in CA1 pyramidal neurons at PD7 and PD30 and prevents deficits in hippocampus-dependent cognitive behavior at PD30. This proposal will unveil novel astrocyte-mediated effects of developmental ethanol exposure on extracellular proteases leading to changes in neuronal development and behavior. The proposed studies will identify cellular (astrocytes) and molecular (ADAMTS5 and tPA) targets of intervention to be tested in future renewals. Significance and Impact to Veterans Healthcare: This proposal encompasses two VA research priorities: 1) Women veterans’ health; 2) Modifiable risk factors. Increased rates of alcohol use disorder (AUD) were reported in women veterans, and a recent study found a lifetime AUD rate of 27% in men and women veterans (historically, rates for men have been higher than women). Alcohol use during pregnancy can lead to Fetal Alcohol Spectrum Disorders (FASD) characterized by structural and life-long impairments of neurocognition, self-regulation, and adaptive functioning. Moreover, FASD is associated with a large number of co-morbidities including depression, anxiety, and other mental illnesses. Women veterans’ reproductive health, including pregnancy, pregnancy outcomes, newborn care, and associated mental health problems, has been identified as an ongoing gap in women veterans’ health. Several recent studies investigated pregnancy outcomes in women veterans where PTSD and life stressors were identified as predictors of postpartum alcohol misuse and of negative maternal and infant outcomes. Moreover, children with FASD present challenges for their caregivers, and women veterans parenting FASD children and adolescents may experience increased levels of stress and feelings of isolation. The identification of mechanisms by which alcohol alters brain development that will guide prevention and early interventions is therefore a topic highly relevant to the VA research mission. Path to translation/implementation: In the current proposal, we will identify cellular and molecular targets of ethanol effects using highly specific molecular tools, i.e. knock-out of target proteins in a cell-type specific manner (substage T0-2 of translatability). In the next renewal we plan on moving our studies to the substage T0-3 of translatability by testing different doses of pharmacological compounds that inhibit tPA and/or ADAMTS5 administered at different stages of brain development with the goal of determining the conditions of maximal effectiveness in reverting the effects of developmental alcohol exposure.