Anales RANF

P.36 ADENOSINERGIC SYSTEM: NOVEL THERAPEUTIC TARGET FOR RETT SYNDROME C. Miranda-Lourenço 1,2 , S.T. Duarte 1,2 , C Palminha 1,2 , M Colino-Oliveira 1,2 , R Gomes 2 , TM Rodrigues 1,2 , S Xapelli 1,2 , LV Lopes 2 , AM Sebastião1,2, M.J. Diógenes 1,2 1 Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Instituto de Medicina Molecular, Universidade de Lisboa, Portugal; 2 Instituto de Medicina Molecular |João Lobo Antunes, Universidade de Lisboa, Portugal. Rett syndrome (RTT) is genetic disorder that originates severe intellectual disabilities besides other symptoms such as epilepsy, developmental stagnation, loss of hand skills, development of stereotypic hand movements and social withdrawal . RTT is mainly caused by mutations in the X-linked MECP2 gene, which leads to impairment of signaling of the neurotrophin brain-derived neurotrophic factor (BDNF). The increase of BDNF signaling in RTT 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 A 1 R it has antiepileptic actions and through A 2A R it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the the adenosinergic and BDNF signaling in RTT and explored whether the activation of A 2A R could boost BDNF action in a RTT animal model, the Mecp2 knockout ( Mecp2 -/y ) (B6.129P2 (C)- Mecp2tm1.1Bird/J) mouse. Whenever possible, parallel data was also obtained from post-mortem brain samples from a RTT patient. The results show that BDNF facilitatory actions upon long-term potentiation (LTP) were absent in the RTT model. In the mice model there was also a significant reduction in TrkB full length (TrkB-FL) receptors levels and a tendency for compensatory alterations in TrkB-FL mRNA, detected both in mouse and human samples. Data obtained suggest a reduction on adenosine levels, and a consequent decrease of inhibitory adenosinergic tonus via A 1 R and A 2A R, which was further aggravated by a significant decrease in the A 2A R receptor protein levels. Remarkably, activation of A2AR with the selective agonist, CGS2168, rescued BDNF effect upon LTP. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A 2A R as therapeutic targets in this devastating pathology. Funding: AdoRett - LISBOA-01-0145-FEDER-031929, Fundação para a Ciência e Tecnologia Regulation of adenosine levels as a new therapeutic strategy for Rett Syndrome, Association française du syndrome de rett SynaNet – Twinning Action (GA-692340), European Union’s H2020 GAPIC, Faculdade de Medicina da Universidade de Lisboa