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

Abstract

AbstractZinc (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 densityin 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.