Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain

Clare Wilhelm, Joel G. Hashimoto, Melissa L. Roberts, Xiaolu Zhang, Calla M. Goeke, Shelley H. Bloom, Marina Guizzetti

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive dysfunction. Neuronal plasticity is affected by in utero alcohol exposure and can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease whose activation is tightly regulated by the plasminogen activator (PA) system. In the present study we explored the effect of ethanol on the expression of the main components of the brain PA system in sex-specific cortical astrocyte primary cultures in vitro and in the cortex and hippocampus of post-natal day (PD) 9 male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently upregulated by ethanol in astrocytes in vitro and in the cortex and hippocampus in vivo. Astrocytes exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hippocampus in vivo. All components of the PA system investigated, with the exception of Neuroserpin/Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting that astrocytes are major producers of these proteins in the brain. In conclusion, astrocyte PA system may play a major role in the modulation of neuronal plasticity; ethanol-induced upregulation of tPA levels and plasmin activity may be responsible for altered neuronal plasticity in FASD.

Original languageEnglish (US)
Pages (from-to)193-209
Number of pages17
JournalNeuropharmacology
Volume138
DOIs
StatePublished - Aug 1 2018

Fingerprint

Plasminogen Activators
Astrocytes
Homeostasis
Ethanol
Brain
Neuronal Plasticity
Fibrinolysin
Fetal Alcohol Spectrum Disorders
Hippocampus
Alcohols
Serine Proteases
Tissue Plasminogen Activator
Proteolysis
Up-Regulation
Genes

Keywords

  • Astrocytes
  • Ethanol
  • Extracellular matrix
  • Fetal alcohol spectrum disorders
  • Plasmin
  • Plasminogen activator system
  • Tissue-type plasminogen activator

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain. / Wilhelm, Clare; Hashimoto, Joel G.; Roberts, Melissa L.; Zhang, Xiaolu; Goeke, Calla M.; Bloom, Shelley H.; Guizzetti, Marina.

In: Neuropharmacology, Vol. 138, 01.08.2018, p. 193-209.

Research output: Contribution to journalArticle

Wilhelm, Clare ; Hashimoto, Joel G. ; Roberts, Melissa L. ; Zhang, Xiaolu ; Goeke, Calla M. ; Bloom, Shelley H. ; Guizzetti, Marina. / Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain. In: Neuropharmacology. 2018 ; Vol. 138. pp. 193-209.
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