1. Pediatric Neurology Department, Hospital D. Estefânia-CHLC.
2. Instituto de Medicina Molecular, Universidade de Lisboa and Hospital de Dona Estefânia, CHLC, Lisbon, Portugal.
3. Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
4. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
5. Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona and CIBER-ER (Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III), Madrid, Spain.
- 11th European Paediatric Neurology Society (EPNS) Congress. 27-30 Maio de 2015, Vienna, Austria (poster)
- Published Abstract: European Journal of Paediatric Neurology 2015; 19:S149
Rett syndrome (RTT) is the main cause of intellectual disability in females and is caused mainly by mutations in the X-linked MECP2 gene. In RTT, brain-derived neurotrophic factor (BDNF) signaling is impaired. BDNF regulates neuronal survival, differentiation and synaptic plasticity such as long-term potentiation (LTP), 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 (R). The activation of A2AR potentiates BDNF synaptic actions in healthy animals. Therefore, we explored whether the activation of A2AR facilitates BDNF action upon LTP in a RTT animal model. MECP2 Knockout (KO) (B6.129P2 (C)-Mecp2tm1.1Bird/J) animals were used for neurophysiological and molecular assay. BDNF facilitatory actions upon LTP are absent in the RTT 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 RTT 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 A2AR agonist, CGS2168, the BDNF effect upon LTP was restored, similar to what was observed in hippocampal slices from WT animals with BDNF alone.
Together our data highlight A2AR as new possible therapeutic targets for boosting BDNF effects in RTT.