# Glia-neuron interaction in fetal alcohol spectrum disorders

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2022 · —

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10476339
- **Project number:** 5I01BX001819-09
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Marina Guizzetti
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476339

## Citation

> US National Institutes of Health, RePORTER application 10476339, Glia-neuron interaction in fetal alcohol spectrum disorders (5I01BX001819-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476339. Licensed CC0.

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