The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

Frazzini, V.; Granzotto, A.; Bomba, M.; Massetti, N.; Castelli, V.; d'Aurora, M.; Punzi, M.; Iorio, M.; Mosca, A.; Delli Pizzi, S.; Gatta, V.; Cimini, A.; Sensi, S. L.

doi:10.1101/267609

bioRxiv · 10.1101/267609

The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

Frazzini, V.·Granzotto, A.·Bomba, M.·Massetti, N.·Castelli, V.·d'Aurora, M.·Punzi, M.·Iorio, M.·Mosca, A.·Delli Pizzi, S.·Gatta, V.·Cimini, A.·Sensi, S. L.

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Abstract

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo.\n\nOur study highlights the importance of choosing \"when\", \"where\", and \"how much\" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development.

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Frazzini, V., Granzotto, A., Bomba, M., Massetti, N., Castelli, V., d'Aurora, M., Punzi, M., Iorio, M., Mosca, A., Delli Pizzi, S., Gatta, V., Cimini, A., Sensi, S. L.. 2018-02-18. The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice. https://doi.org/10.1101/267609

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