Anales RANF

P.10 PHARMACOLOGICAL BLOCKADE OF ADENOSINE A 2A RECEPTORS RECOVERS MOTOR LEARNING AND GRIP STRENGTH DEFICITS IN AN ANGELMAN SYNDROME MOUSE MODEL AM de Sá 1,2 , FQ Gonçalves 1 , JP Lopes 1 , HB Silva 1 , ÂR Tomé 1,2 , RA Cunha 1,3 & PM Canas 1 1 CNC-Center for Neuroscience and Cell Biology, Coimbra, Portugal; 2 Faculty of Sciences and Technology, University of Coimbra, Portugal; 3 Faculty of Medicine, University of Coimbra, Portugal. Angelman syndrome (AS) is a rare neurodevelopmental disorder resulting from a loss of function of neuronal Ube3A protein. A 2A receptor (A 2A R) antagonists can counteract locomotor deficits in mouse models of different brain diseases. As AS therapeutics has been met with limited success, we here hypothesized that an adenosine-based strategy could also ameliorate the motor impairments in the AS animal model. We used Ube3A m-/p+ modelling AS and wild-type (WT) littermates mice, at 8 weeks of age. In an accelerated rotarod test, AS mice had a lower performance as compared to their WT littermates (33.2±7.8 s in AS vs. 67.0±9.0 s in WT, when measuring latency to fall in the first day, with differences persisting across the days, n=13-16, p<0.01). Additionally, AS mice displayed decreased strength in a grasping protocol (2.9±0.1 kg- force/kg vs. 3.7±0.1 kg-force/kg, n=7-13, p<0.0001) and displayed lower locomotor activity in the open field (22.1±1.4 m vs. 26.4±1.3 m, n=19-25, p<0.05). Next, we checked if the by daily intraperitoneal injections of the A 2A R selective antagonist SCH58261 (0.1 mg/kg, for 21 days) could revert the impairments found in AS mice. SCH58261 attenuated the motor learning deficits of AS mice, since SCH58261-treated AS mice improved their rotarod performance (34.2±6.2 s in day 1 vs. 65.7±13.3 s in day 3, n=9, p<0.01) while the saline-treated AS mice were not able to learn in the rotarod (40.3±8.2 s in day 1 vs. 44.2±4.9 s in day 3, n=9). SCH58261 also rescued grip strength impairment (difference between grip strength values in the post and pre-treatment: 0.42±0.25 kg-force/kg in SCH58261-treated AS mice vs. -0.44±0.24 kg-force/kg in saline-treated AS mice, n=9-11, p<0.05). Thus, we propose that the blockade of A 2A R can ameliorate the motor and coordination deficits found in this AS mice model. Supported by Fundação Amélia de Mello and CENTRO-01-0246-FEDER-000010.