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

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.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…In SHSY5Y cells, Cu 2+ treatment decreased pro-BDNF level in cells and increased pro-and mature BDNF levels in the medium [128] with a strong decrease of the proliferative activity of both cleaved BDNF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and the full length protein [129]. Application of zinc chelator induced reduction of BDNF level, synaptic plasticity-related proteins and dendritic spine density in vivo, which further confirm that appropriate amount of Zn 2+ is essential in brain development and the synaptic functions [130].…”

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction

“…The expression and activation of these proteins are crucial for the processes of neuroplasticity, which are perturbed in animal models of depression [23]. Moreover, the disruption of neuroplasticity defined as a decrease in synaptic plasticity-related proteins and reduced density of synaptic spines has been reported in ZnD mice, induced by the chronic administration of clioquinol, a known Zn/copper chelator [46]. Since a dysfunction in neural plasticity has been reported in the Hp and PFC in animal models of depression [47,48], we chose these same regions for our assays.…”

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

“…Depletion of zinc levels in the brain of young mice (2.5 months old) using the zinc/copper chelator clioquinol impaired short-and long-term memory performance. Mechanistically, treatment with clioquinol reduced levels of brain derived neurotrophic factor (BDNF), synaptic plasticity-related proteins and dendritic spine density in vivo [163] . These changes were regionally restricted to the hippocampus, cortex, and striatum, without having any effects on the cerebellum, an area devoid of pools of cheatable zinc [163,164] .…”

“…Mechanistically, treatment with clioquinol reduced levels of brain derived neurotrophic factor (BDNF), synaptic plasticity-related proteins and dendritic spine density in vivo [163] . These changes were regionally restricted to the hippocampus, cortex, and striatum, without having any effects on the cerebellum, an area devoid of pools of cheatable zinc [163,164] . These results support the notion that zinc is an important modulator of synaptic plasticity, neurotransmission, neuronal function and cognitive processes in the brain, and highlights the potential detrimental consequences of reducing the availability of zinc in the brains of healthy individuals or in the early stages of AD.…”