Evidence for aberrant astrocyte hemichannel activity in juvenile neuronal ceroid lipofuscinosis (JNCL)

Maria Burkovetskaya, Nikolay Karpuk, Juan Xiong, Megan Bosch, Michael D. Boska, Hideyuki Takeuchi, Akio Suzumura, Tammy L Kielian

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.

Original languageEnglish (US)
Article numbere95023
JournalPloS one
Volume9
Issue number4
DOIs
StatePublished - Apr 15 2014

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
astrocytes
Astrocytes
Wild Animals
gap junctions
Gap Junctions
mice
Brain
Animals
brain
animal communication
Communication
Carbenoxolone
Lysosomal Storage Diseases
mutation
connexins
animals
Glutamate-Ammonia Ligase
Mutation

ASJC Scopus subject areas

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

Cite this

Evidence for aberrant astrocyte hemichannel activity in juvenile neuronal ceroid lipofuscinosis (JNCL). / Burkovetskaya, Maria; Karpuk, Nikolay; Xiong, Juan; Bosch, Megan; Boska, Michael D.; Takeuchi, Hideyuki; Suzumura, Akio; Kielian, Tammy L.

In: PloS one, Vol. 9, No. 4, e95023, 15.04.2014.

Research output: Contribution to journalArticle

Burkovetskaya, M, Karpuk, N, Xiong, J, Bosch, M, Boska, MD, Takeuchi, H, Suzumura, A & Kielian, TL 2014, 'Evidence for aberrant astrocyte hemichannel activity in juvenile neuronal ceroid lipofuscinosis (JNCL)', PloS one, vol. 9, no. 4, e95023. https://doi.org/10.1371/journal.pone.0095023
Burkovetskaya M, Karpuk N, Xiong J, Bosch M, Boska MD, Takeuchi H et al. Evidence for aberrant astrocyte hemichannel activity in juvenile neuronal ceroid lipofuscinosis (JNCL). PloS one. 2014 Apr 15;9(4). e95023. https://doi.org/10.1371/journal.pone.0095023
Burkovetskaya, Maria ; Karpuk, Nikolay ; Xiong, Juan ; Bosch, Megan ; Boska, Michael D. ; Takeuchi, Hideyuki ; Suzumura, Akio ; Kielian, Tammy L. / Evidence for aberrant astrocyte hemichannel activity in juvenile neuronal ceroid lipofuscinosis (JNCL). In: PloS one. 2014 ; Vol. 9, No. 4.
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