Substance use disorders are common among women veterans, many of which are of childbearing age. Drinking during pregnancy may lead to Fetal Alcohol Spectrum Disorders (FASD), a leading cause of intellectual disability. Research on novel mechanisms involved in FASD, which may lead to innovative interventions, is therefore a topic highly relevant to the VA mission. Hippocampal alterations are associated with deficits in learning and memory in individuals with FASD. The extracellular matrix (ECM) plays a major role in brain development and astrocytes are major regulators of the brain ECM. Critical gaps in knowledge remain concerning the mechanisms by which ethanol alters neuronal development in the fetal hippocampus hampering the development of therapies for FASD. Indeed, there is no published literature on the effects of alcohol exposure during the third trimester of human gestation-equivalent on astrocyte gene expression in vivo. Furthermore, dysregulation of the brain ECM mediated by alterations in extracellular proteases is involved in many neuropathological conditions and in addiction. However, very little is known about the role of the ECM and extracellular proteases in FASD in vivo. Finally, the link between changes in astrocyte-released ECM modulators and dendritic development following neonatal alcohol exposure has not been investigated. Preliminary results suggest that developmental alcohol exposure alters the ECM through the modulation of extracellular protease systems in the hippocampus. Indeed, Adamts5 expression, encoding for a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a protease that degrades lecticans, and tissue plasminogen activator (tPA), which can activate ADAMTSs, are both upregulated in the hippocampus of animals neonatally exposed to ethanol. Furthermore, we observed decreased levels of lectican sulfated glycosaminoglycans (sGAGs) and increased proteolysis of the lectican brevican in these animals. We also observed down-regulation of Mmp14 and Mmp15 encoding for matrix metalloproteinases (MMP)14 and MMP15 and increased protein levels of one major target of these MMPs: laminin. All of these changes are consistent with an ethanol-induced increase in dendritic arborization in pyramidal hippocampal neurons, as lecticans are inhibitors and laminin is a strong inducer of dendritic arborization. The overall hypothesis of this proposal is that ethanol alters the expression and activity of astrocyte extracellular proteases leading to ECM remodeling and increased dendritic arborization in the hippocampus. In aim 1, the hypothesis that developmental ethanol exposure increases the expression and activity of ADAMTSs that degrade lecticans in part via an increase in tPA expression leading to ADAMTS activation resulting in the degradation of lecticans and increased dendritic arborization in the neonatal brain will be explored. In aim 2, the hypothesis that ethanol exposure decreases MMP14 and MMP15 leading to ...