Disruption in Connexin-Based Communication Is Associated with Intracellular Ca2+ Signal Alterations in Astrocytes from Niemann-Pick Type C Mice

Pablo J. Sáez, Juan A. Orellana, Natalia Vega-Riveros, Vania A. Figueroa, Diego E. Hernández, Juan F. Castro, Andrés D. Klein, Jean X. Jiang, Silvana Zanlungo, Juan C. Sáez

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1-/-) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1-/- hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1-/- astrocytes also showed more intracellular Ca2+ signal oscillations mediated by functional connexin 43 hemichannels and P2Y1 receptors. Therefore, Npc1-/- astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

Original languageEnglish (US)
Article numbere71361
JournalPloS one
Volume8
Issue number8
DOIs
StatePublished - Aug 15 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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