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

  • Author(s): Frazzini, Valerio
  • Granzotto, Alberto
  • Bomba, Manuela
  • Massetti, Noemi
  • Castelli, Vanessa
  • Castelli, Vanessa
  • d'Aurora, Marco
  • Punzi, Miriam
  • Iorio, Mariangela
  • Mosca, Alessandra
  • Delli Pizzi, Stefano
  • Gatta, Valentina
  • Cimini, Annamaria
  • Sensi, Stefano L
  • et al.
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 signaling, 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. Our 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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