1- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Portugal; 2 - Hospital Dona Estefânia, Centro Hospitalar Lisboa Central, Lisboa, Portugal; 3- Neurology Department, Synaptic Metabolism Laboratory, Hospital San Joan de Déu, Barcelona, Spain
- 9th FENS Forum of Neuroscience, 5-9 Julho, Milão, Itália
Rett syndrome (RTT) is the major cause of intelectual disability in females. In RTT, brain-derived neurotrophic factor (BDNF) signaling is impaired. BDNF regulates neuronal survival, differentiation and synaptic plasticity such as long-term potentiation (LTP) which is accepted as the neurophysiological basis for learning and memory. The increase of BDNF signaling would be a great breakthrough, but has been hampered by the difficulty to administer BDNF. The activation of adenosine A2A receptors (A2AR) potentiates BDNF synaptic actions in healthy animals. Therefore we explored whether the activation of A2AR facilitates BDNF action upon LTP.
Field-excitatory post-synaptic potentials were recorded from the CA1 area of hippocampal slices taken from wild type (WT) or MECP2-null mice (RTT model) in two different developmental stages: (pre-symptomatic: 3 week-old and symptomatic: 6 week-old animals). LTP was induced by theta-burst stimulation in two independent pathways.
Hippocampal LTP recorded from pre-symptomatic animals is preserved in RTT model when compared to aged matched WT animals. However exogenous BDNF (20ng/ml) does not have the expected excitatory effect as detected in WT animals. In symptomatic animals, hippocampal LTP is impaired in RTT mice model when compared to aged matched WT animals. BDNF exogenously added to hippocampal slices taken from MECP2 null mice does not further increase LTP magnitude as in WT. Accordingly to our preliminary data, the activation of A2ARby the selective agonist CGS2168 (10nM) facilitates the excitatory effect of BDNF upon LTP.
BDNF signaling modulation, through A2AR activation, is a promising therapeutic approach for RTT.
Palavras Chave: Receptores adenosina, Síndroma de Rett, BDNF