Anales RANF

P.52 SYNAPTIC DYSFUNCTIONS AT THE HIPPOCAMPUS OF AN AMYOTROPHIC LATERAL SCLEROSIS MOUSE MODEL (SOD1 G93A ): REVERSAL BY ADENOSINE A 2A R BLOCKADE N.Rei 1,2, D.M. Rombo 1,2, Y. Baqi 3, C.E . Müller 4, J.A. Ribeiro 1,2 , A.M. Sebastião 1,2, S.H. Vaz 1,2 1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal; 2Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; 3Faculty of Science, Sultan Qaboos University, Muscat, Oman; 4Pharmazeutisches Institut,, University of Bonn, Germany. Amyotrophic Lateral Sclerosis (ALS) is mainly a motor disease, although extramotor neural and cognitive alterations have also been reported. Our aim was to access the changes in the activity and plasticity of synapses in SOD1 G93A mice through disease progression. We then assessed how those changes could be modified by an antagonist of a receptor frequently involved in excitotoxicity, the adenosine A 2A receptor, which is overexpressed and/or overactivated in SOD1 G93A mice and in ALS patients. Field-excitatory post-synaptic potentials (fEPSP) were recorded in hippocampal slices from SOD1 G93A mice at pre-symptomatic (4-6 W) and symptomatic (14-18 W) stages, and from age-matched wild- type mice. θ -burst-induced LTP and paired-pulse facilitation (PPF) were recorded as previously . Statistical analysis was by the student’s t -test while comparing two groups or one-way ANOVA for multiple comparisons. There were no significant differences between the magnitude of LTP in pre- symptomatic and WT mice. In symptomatic mice, LTP magnitude was significantly decreased as compared with age-matched WT, indicating an impairment of synaptic plasticity. PPF was significantly decreased in pre-symptomatic mice when compared with age-matched WT, indicating an enhanced synaptic excitability in early disease stages. In symptomatic mice, PPF values were not significantly different from those obtained in WT mice . In symptomatic SOD1 G93A mice chronically treated with the A 2A R antagonist, KW- 6002, the decrease in LTP was no longer detected, as compared with WT mice similarly treated, suggesting that A 2A R blockade could prevent the impairment in synaptic plasticity in ALS. Treatment with the A 2A R antagonist did not affect basal synaptic transmission or PPF values in any group of animals . The results suggest an enhanced transmitter release in pre-symptomatic stage followed by a decrease in synaptic plasticity in the symptomatic stage. This may result from A 2A R over activation in early disease stages.