Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.The work was supported by a joint research grant awarded to TMR from Fundação Calouste Gulbenkian and FMUL (20130002/PEC/BG); Fundação para a Ciência e Tecnologia (FCT, AdoRett – LISBOA-01-0145-FEDER-031929/2017 and FCT SFRH/BD/118238/2016 granted to CML); Universidade de Lisboa (grant awarded by CML BD2015); the Association Française du Syndrome de Rett; Program “Educação pela Ciência” Bolsas CHLN/FMUL – GAPIC (Project No. 20190017); Twinning action (SynaNet) from the EU H2020 Programme; and the UID/BIM/50005/2019, project financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Fundos do Orçamento de Estado. The work performed at ICBAS/MedInUP by PCS and TMC was partially supported by FCT (FEDER funding, project UID/BIM/4308/2019 and UIDP/04308/2020).