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

Mol Psychiatry. 2020 Aug;25(8):1876-1900. doi: 10.1038/s41380-018-0110-9. Epub 2018 Jun 27.

Abstract

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 Ca2+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Aging / metabolism*
  • Alzheimer Disease / metabolism
  • Animals
  • Cells, Cultured
  • Hippocampus / metabolism
  • Humans
  • Long-Term Synaptic Depression*
  • Mice
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Spatial Memory

Substances

  • Receptor, Adenosine A2A
  • Receptor, Metabotropic Glutamate 5
  • Receptors, N-Methyl-D-Aspartate
  • Adenosine