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 A receptor (AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of AR in age-related conditions. We report, for the first time, a significant overexpression of AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of AR 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 influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon AR blockade. This AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Adenosine A1 and A2A receptors differently control synaptic plasticity in the mouse dorsal and ventral hippocampus

“…Previous studies have proposed that A 1 R are mainly associated with the modulation of basal synaptic transmission, whereas A 2A R have a more prominent role in controlling processes of synaptic plasticity (Rebola et al, ; Fontinha et al, ; Costenla et al, ; Temido‐Ferreira et al, ). Thus, we first compared the efficiency of A 1 R to inhibit basal transmission in DH and VH, by acutely exposing DH or VH slices to the adenosine analogue 2‐choloroadenosine.…”

“…Based on the input‐output curves, choose a stimulus that evoked a signal of circa 40% (for long‐term potentiation (LTP) and paired‐pulse ratio) or circa 60% [for long‐term depression (LTD)] of the maximal slope was chosen. The paired‐pulse ratio was investigated by applying two pulses with an interpulse interval of 20, 40, 100, or 200 ms. LTP was induced by applying a high frequency stimulation (HFS) consisting of a single train of pulse at 100 Hz for 1 s. LTD was induced by applying a low frequency stimulation (LFS) protocol consisting of 3 trains of 1500 pulses at 2 Hz each, with intertrain interval of 10 min (van der Jeugd et al, ; Temido‐Ferreira et al, ). The LTP and of LTD magnitude was evaluated by comparing the average of the fEPSP slopes from 50 to 60 min after HFS or LFS with the average of the fEPSP slopes 10 min before the HFS or LFS (baseline) and is represented as percentage of change from baseline.…”

Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat

“…As indicated above, it may well be that changes in the extracellular calcium concentration imposes metaplastic changes that result in new set points for the induction of various forms of long‐lasting synaptic depression and potentiation (Temido‐Ferreira et al . ).…”

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

“…The relationship between A 2A R and AD in the control of cognitive impairment has been extensively observed in several experimental models (Canas et al, 2009;Laurent et al, 2014;Laurent et al, 2014;Lee et al, 2018;Silva et al, 2018). Upregulation of A 2A R in neurons was shown to induce aberrant phenotypic alterations during aging and in the early stages of AD (Temido-Ferreira et al, 2018). Early A 2A R downregulation in neurons is sufficient to abrogate alterations of synaptic plasticity and memory in an animal model of amyloidogenesis (Viana da Silva et al, 2016).…”

“…The effects of adenosine in the brain are essentially mediated through the activation of A 1 and A 2A receptors. In physiological conditions, A 2A Rs play an important role in fine synaptic tuning (Cunha, 2016): neuronal A 2A Rs regulated NMDA receptors to control synaptic plasticity processes (Rebola et al, 2008;Temido-Ferreira et al, 2018) while astrocytic A 2A Rs control glutamate and GABA uptakes (Lopes et al, 2002;Matos et al, 2012Matos et al, , 2013Cristovao-Ferreira et al, 2013), regulating the excitatory/inhibitory balance. Interestingly, reactive astrocytes have been shown to exhibit adenosine A 2A R upregulation in different neuropathological conditions such as AD, epilepsy, Sandhoff disease, and also in animal models of AD and PD (Orr et al, 2015(Orr et al, , 2018Barros-Barbosa et al, 2016;Zhao et al, 2017;Faivre et al, 2018;Lee et al, 2018;Yu et al, 2008;Hu et al, 2016;Ogawa et al, 2018).…”