Opera Medica et Physiologica

Inhibition of Glycogen Synthase Kinase 3 Prevents Synaptic Long- Term Depression and Facilitates Cognition in C57bl/6J Mice

Author Affiliations

Tatiana V. Lipina1,2 *

Maria Jekielek3

Nikolay A. Beregovoy1,4

Marina V. Starostina1,4

Valle Palomo

Daniel I Perez5 

Ana Martinez

John C Roder2,6

1 Federal State Budgetary Scientific Institution, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, 630117,
2 Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada;
3 Jagiellonian University Medical College, Świętej Anny 12, 31-008 Kraków, Poland;
4 Federal State Budgetary Scientific Institution, Institute of Molecular Biology and Biophysics, Novosibirsk, 630117, Russia;
5 Centro de investigaciones Biologicas-CSIC, Madrid, Spain;
6 University of Toronto, Departments of Medical Biophysics and Molecular & Medical Genetics, Toronto, Ontario, M5S 1A1, Canada.

Corresponding author: 

Tatiana V. Lipina (lipina@physiol.ru)


Glycogen synthase kinase 3 (GSK-3) is an important molecular player involved into diverse cellular functions including metabolism, transcription, cell survival and synaptic plasticity. Here, we focused on characterization of the cognitive effects of GSK-3 inhibitor, a newly developed compound VP3.36. In particular, we assessed VP3.36 effects on working memory, episodic memory, executive functioning, spatial learning & memory and fear memory. VP3.36 (3 mg/kg) significantly enhanced working memory and spatial object recognition in C57BL/6J mice. The GSK-3 inhibitor was able to speed up solving obstacles given to experimental animals in the Puzzle test, thereby improving their executive functions. Lastly, VP3.36-treated mice learnt faster to find the escape platform in the Morris’ water maze and exhibited better spatial long-term memory than vehicle-treated animals. At the same time, GSK-3 inhibition did not affect fear memories, sensorimotor gating, emotional behavior or ambulation, suggesting that GSK-3 inhibition underlies specific cognitive processes, which are likely coupled with certain mechanisms of synaptic plasticity. Given that GSK-3 inhibition has clear effect on long-term depression (LTD), and the functional role of LTD in brain is still far from complete understanding, next, we probed effects of VP3.36 on synaptic LTD in the hippocampal CA1 subregion. We found that incubation of hippocampal slices with VP3.36 sufficiently prevented synaptic LTD, further supporting implication of GSK-3 into mechanisms of synaptic plasticity. Taken together, VP3.36 facilitated working memory, spatial episodic and long-term memory, enhanced executive functions in parallel with its ability to prevent synaptic LTD. Overall, our experiments showed implication of GSK-3 into mechanisms of synaptic plasticity and certain cognitive functions which help to deeper understand fundamental molecular-cellular mechanisms of cognitive enhancement’s processes.