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PGC-1 alpha Signaling Increases GABA(A) Receptor Subunit alpha 2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice

Authors
  • Vanaveski, Taavi
  • Molchanova, Svetlana
  • Duc Pham, Dan
  • Schafer, Annika
  • Pajanoja, Ceren
  • Narvik, Jane
  • Srinivasan, Vignesh
  • Urb, Mari
  • Koivisto, Maria
  • Vasar, Eero
  • Timmusk, Tonis
  • Minkeviciene, Rimante
  • Eriksson, Ove
  • Lalowski, Maciej
  • Taira, Tomi
  • Korhonen, Laura
  • Voikar, Vootele
  • Lindholm, Dan
Publication Date
Jan 01, 2021
Identifiers
DOI: 10.3389/fnmol.2021.588230
OAI: oai:DiVA.org:liu-173884
Source
DiVA - Academic Archive On-line
Keywords
Language
English
License
Green
External links

Abstract

Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1 alpha expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of gamma-aminobutyric acid (GABA) type A receptor-alpha 2 subunit (GABAR alpha 2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1 alpha in neurons. Along with this, GABAR alpha 2 expression was enhanced in the hippocampus of the PGC-1 alpha Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABAR alpha 2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1 alpha Tg mice compared with controls. To study whether drugs acting on PPAR gamma can affect GABAR alpha 2, we employed pioglitazone that elevated GABAR alpha 2 expression in primary cultured neurons. Similar results were obtained using the specific PPAR gamma agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1 alpha regulates GABAR alpha 2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABAR alpha 2 expression via the PPAR gamma/PGC-1 alpha system. / <p>Funding Agencies|EUEuropean Commission [H2020-MSCA-RISE-2016, 734791]; European Regional Development FundEuropean Commission [2014-2020-4-01.15-0012]; Liv and the Halsa Foundation; Academy of FinlandAcademy of FinlandEuropean Commission [290608]; Finska Lakaresallskapet; Magnus Ehrnrooth Foundation; Minerva Foundation; Estonian Research CouncilEstonian Research Council [PRG805]; Biocenter Finland; Helsinki Institute of Life Science</p>

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