Calcineurin/NFAT signaling in activated astrocytes drives network hyperexcitability in Aβ-bearing mice

Pradoldej Sompol, Jennifer L. Furman, Melanie M. Pleiss, Susan D. Kraner, Irina A. Artiushin, Seth R. Batten, Jorge E. Quintero, Linda A. Simmerman, Tina L. Beckett, Mark A. Lovell, M. Paul Murphy, Greg A. Gerhardt, Christopher M. Norris

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer’s disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin(CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with microelectrode arrays and ex vivo brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD.

Original languageEnglish
Pages (from-to)6132-6148
Number of pages17
JournalJournal of Neuroscience
Volume37
Issue number25
DOIs
StatePublished - Jun 21 2017

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants AG027297 and AG051945 to C.M.N. and Grant AG000242-20 to P.S.; and The Hazel Embry Research Trust. We thank Drs. Eric M. Blalock and Richard Kryscio for conceptual and statistical input.

Publisher Copyright:
© 2017 the authors.

Keywords

  • Alzheimer’s disease
  • Astrocytes
  • Calcineurin
  • Dementia
  • Glutamate
  • Hyperexcitability

ASJC Scopus subject areas

  • Neuroscience (all)

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