P197 – 3009: Adenosine receptors as new therapeutic targets in Rett syndrome

• Published in: European journal of paediatric neurology 2015-05, Vol.19, p.S149-S149
• Main Authors: Duarte, S.T, Palminha, C, Sebastião, A.M, Diogenes, M.J
• Format: Article
• Language: English
• Subjects: Neurology; Pediatrics
• ISSN: 1090-3798; 1532-2130
• DOI: 10.1016/S1090-3798(15)30510-9

Objective Rett syndrome is the main cause of intellectual disability in females and is caused mainly by mutations in the X-linked MECP2 gene. In Rett syndrome, brain-derived neurotrophic factor (BDNF) signaling is impaired. BDNF regulates neuronal survival, differentiation and synaptic plasticity such as long-term potentiation, accepted as the neurophysiological basis for learning and memory. The increase of BDNF signaling would be a significant breakthrough, but has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine is a neuromodulator that acts mainly through A1 and A2A receptors. The activation of A2A receptors potentiates BDNF synaptic actions in healthy animals. Therefore, we explored whether the activation of A2AR facilitates BDNF action upon long term potentiation in a Rett Syndrome animal model. Methods MECP2 Knockout (B6.129P2 (C)-Mecp2tm1.1Bird/J) animals were used for neurophysiological and molecular assay. Results BDNF facilitatory actions upon long term potentiation are absent in the Rett Syndrome animal model. This dysfunction could be explained by a reduction in TrkB full length receptors levels, described for the first time in the present study. Additionally, we found that adenosinergic system is also compromised in the Rett syndrome model with a possible reduction on adenosine levels and a consequent decrease of inhibitory adenosinergic tonus via A1R and A2AR. When BDNF was combined with the selective A2A receptor agonist, CGS2168, the BDNF effect upon long term potentiation was restored, similar to what was observed in hippocampal slices from wild type animals with BDNF alone. Conclusion Together, our data highlight A2A receptors as new possible therapeutic targets for boosting BDNF effects in Rett syndrome.