Genetic removal of synaptic Zn2+ impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity

Abstract

Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Here we report that the genetic removal of synaptic Zn2+ results in progressive impairment of hippocampal-dependent memory, reduces activity-dependent increase in Erk phosphorylation and BDNF mRNA, alters regulation of Erk activation by NMDAR subunits, increases neuronal spiking, and induces biochemical and morphological alterations consistent with increasing epileptiform activity and neurodegeneration as ZnT3KO mice age. Our study shows that disruption of synaptic Zn2+ triggers neurodegenerative processes and is a potential pathway through which AβO trigger altered expression of neurotrophic proteins, along with reduced hippocampal synaptic density and degenerating neurons, neuronal spiking activity, and cognitive impairment and supports efforts to develop therapeutics to preserve synaptic zinc homeostasis in the brain as potential treatments for AD.

Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism

“…Yet, previous investigations provided rather limited data on aged and female mice. Adlard et al ( 2010 ) found a cognitive decline in 3-month-old ZnT mice (mixed-gender) using MWM testing and progressive decline in object location memory (OLM) at 3 and 6-months of age was also reported (also a mixed-gender study; Vogler et al, 2022 ). Here we monitored performance of male and female ZnT mice in NOR, NLR, MWM, Y-, and T-maze tests for up to 9 months of age.…”

“…Importantly, insulin resistance in the brain also can damage hippocampal synaptic plasticity leading to abnormal synaptic function (Stranahan et al, 2008 ; Ansari et al, 2023 ). Morphological development of dendrites in hippocampal neurons is regulated by the brain-derived neurotrophic factor (BDNF) (Wang et al, 2015 ) and there are reports indicating that ZnT 3 knockout mice show reduced BDNF expression (Vogler et al, 2022 ). However other studies reported that knocking out ZnT 3 can lead to an increased levels of BDNF in the brain of younger mice, which was linked to increased dendritic length and more intricate connections between neurons (Helgager et al, 2014 ; Yoo et al, 2016 ; McAllister et al, 2020 ).…”

“…Global ZnT 3 knockout mouse line (ZnT ) was generated in the Palmiter's laboratory (Cole et al, 1999 ) and these were shown to demonstrate some cognitive deficits and decreased synaptic spine density in the hippocampus (Vogler et al, 2022 ). Here, we used ZnT mice to investigate importance of ZnT 3 for cognitive functions, synaptic plasticity and expression of key glucose transporters during mouse development.…”

Unlocking the brain’s zinc code: implications for cognitive function and disease

“…Zn 2+ dyshomeostasis is related to aging within the cerebral cortex, as well. As the cerebral cortex is involved in high levels of cognitive functions, alterations in Zn 2+ levels within this area could impact cognitive performance in elderly individuals (Vogler et al, 2022). Fluctuations in Zn 2+ distribution, transport, and signaling may contribute to age-related cognitive decline, neurodegenerative diseases, and other age-related neuropathological conditions and psychiatric disorders (Takeda et al, 2018;Marchetti et al, 2022).…”