Age-related shift in LTD is dependent on neuronal adenosine A(2A) receptors interplay with mGluR5 and NMDA receptors


  • M. Temido-Ferreira
  • D.G. Ferreira
  • V.L. Batalha
  • I. Marques-Morgado
  • J.E. Coelho
  • P. Pereira
  • R. Gomes
  • A. Pinto
  • S. Carvalho
  • P.M. Canas
  • L. Cuvelier
  • V. Buée-Scherrer
  • E. Faivre
  • Y. Baqi
  • C.E. Müller
  • J. Pimentel
  • S.N. Schiffmann
  • L. Buée
  • M. Bader
  • T.F. Outeiro
  • D. Blum
  • R.A. Cunha
  • H. Marie
  • P.A. Pousinha
  • L.V. Lopes


  • Molecular Psychiatry


  • Mol Psychiatry 25 (8): 1876-1900


  • Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca(2+) influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.