P.3.015 - Selective inhibitors of GSK-3β: a suitable therapy for Down syndrome?

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Introduction Intellectual disability (ID) is the most invalidating feature of Down syndrome (DS), a condition caused by triplication of HSA21. ID is mainly due to early-occurring neurogenesis defects. Despite intense efforts, there are currently no pharmacotherapies for DS. Recent evidence in the Ts65Dn model of DS shows that overactivation of GSK3β, a kinase strongly involved in neurogenesis [1], plays a key role in neurogenesis impairment in DS [2]. Several inhibitors of GSK3β have been developed during the last few years, as a strategy for treating psychiatric disorders. Interestingly, recent evidence in adult rats shows that tideglusib (NP031112), a selective non-ATP competitive GSK3β inhibitor, increases neurogenesis in the hippocampus [3], a region fundamental for long-term memory. Aim Based on these premises, the goal of the current study was to establish whether treatment with tideglusib restores neurogenesis in the hippocampal dentate gyrus (DG) of Ts65Dn mice and whether treatment leads to memory improvement. Methods In vivo study. Four-months-old Euploid (Eu) and Ts65Dn (Ts) mice were i.p. injected with saline (sham), vehicle (corn oil) or vehicle+tideglusib (50 mg/kg) for one month and memory was tested with the Morris Water Maze (MWM). Eu and Ts pups were injected with saline, vehicle or vehicle+tideglusib (50 mg/kg) from postnatal day 3 (P3) to P15. In vitro study. Cultures of NPCs from the subventricular zone of P2 mice were treated with i) tideglusib (0.1-10.0 µM), ii) each of the two main components of corn oil: Oleic Acid (OA; 100 µM) and Linoleic Acid (LA; 100 µM); iii) tideglusib+OA or tideglusib+LA. Statistics. In vivo: three-way mixed ANOVA (learning phase of MWM) and two-way ANOVA (probe test and immunohistochemistry) followed by post hoc Fisher LSD test. In vitro: one-way ANOVA followed by post hoc Tukey test. Results Ts were severely impaired in various learning and memory parameters (p Conclusion The finding that tideglusib does not improve neurogenesis and behavior indicates that it is not a suitable treatment for DS. The finding that the fatty acids present in the vehicle (OA and LA) have a pro-neurogenic effect suggests that agonists of fatty acid receptors may represent a good strategy to ameliorate brain development in individuals with DS.