Meningeal γδ T cells are biased toward IL-17 production and control hippocampal synaptic plasticity and short-term memory.

Consumption of caffeine, a non-selective adenosine A_2A receptor (A_2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A_2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A_2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A_2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A_2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A_2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A_2A receptors as important molecular targets to consider against AD and Tauopathies.

The function of striatal adenosine A_2Areceptors (A_2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A_2ARs and dopamine D₂receptors in the striatum. However, the role of extrastriatal A_2ARs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A_2ARs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A_2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A_2AR knock-out (st-A_2AR KO) mice in comparison with forebrain-specific A_2AR KO (fb-A_2AR KO) mice. In contrast to fb-A_2AR KO (deleting A_2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A_2AR KO mice exhibited Cre-mediated selective deletion of the A_2AR gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A_2AR KO but attenuated in fb-A_2AR KO mice. Furthermore, selective inactivation of the A_2ARs in extrastriatal cells by administering the A_2AR antagonist KW6002 into st-A_2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A_2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A_2ARs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A_2ARs.