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Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors.

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.

SUBMITTER: Temido-Ferreira M

PROVIDER: S-EPMC7387321 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors.

Temido-Ferreira Mariana M Ferreira Diana G DG Batalha Vânia L VL Marques-Morgado Inês I Coelho Joana E JE Pereira Pedro P Gomes Rui R Pinto Andreia A Carvalho Sara S Canas Paula M PM Cuvelier Laetitia L Buée-Scherrer Valerie V Faivre Emilie E Baqi Younis Y Müller Christa E CE Pimentel José J Schiffmann Serge N SN Buée Luc L Bader Michael M Outeiro Tiago F TF Blum David D Cunha Rodrigo A RA Marie Hélène H Pousinha Paula A PA Lopes Luísa V LV

Molecular psychiatry 20180627 8

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 huma ...[more]

PMID: 29950682

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Project description:Strategies are needed to reverse the immune cell hyporesponsiveness and prevent bacterial overgrowth associated with high mortality rates in septic patients. Adenosine signaling may be mediating immunosuppressive signals within the inflammatory microenvironment that are safeguarding bacteria by rendering immune cells hyporesponsive. We examined A2A adenosine receptor (A2AR)-mediated immune responses in a chronic model of cecal ligation and puncture (CLP)-induced sepsis using both wild-type (WT) and A2AR knockout (KO) mice. In this model, chronic bacterial peritonitis was established that results in the first death on day 4. A2A adenosine receptors promoted bacterial overgrowth that was associated with a high 28-day sepsis mortality (WT 87% vs. A2AR KO 13%; P < 0.0001). Chronic bacteremia persisted in both WT and A2AR KO mice over the 28-day study period. Bacteremia was significantly decreased in A2AR KO mice 2 days after antibiotic therapy cessation (day 6 after CLP; P < 0.005). Local and disseminated bacteria levels were compared at the end of the 28-day study period or from moribund mice. A2A adenosine receptor deficiency dramatically decreased peritoneal (P < 0.05), splenic (P < 0.05), and blood (P < 0.01) bacterial levels. A2A adenosine receptor deficiency caused an early reduction in inflammatory mediators IL-6, macrophage inflammatory protein 2, TNF-srI, and TNF-srII (P < 0.05), but not in TNF-?, IL-1?, IL-10, or monocyte chemotactic protein 1 within 24 h after CLP. In response to an intravenous lipopolysaccharide (day 5 after CLP) challenge, A2AR KO mice showed enhanced secretion of TNF-? (2 h), IFN-?, IL-6, monocyte chemotactic protein 1, IL-10, and macrophage inflammatory protein 2 (9 h) (P < 0.05), suggesting that A2ARs attenuate inflammatory responses to repeat infectious insults. These data demonstrate that A2AR blockade may be an effective immunotherapy treatment to prevent bacterial overgrowth and reduce mortality secondary to immunosuppression in septic patients.

Dataset Information

Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors.

Publications

Age-related shift in LTD is dependent on neuronal adenosine A<sub>2A</sub> receptors interplay with mGluR5 and NMDA receptors.

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