Abstract
Zinc (Zn2+) is an integral component of many proteins and has been shown to act in a regulatory capacity in different mammalian systems, including as a neurotransmitter in neurons throughout the brain. While Zn2+ plays an important role in modulating neuronal potentiation and synaptic plasticity, little is known about the signaling mechanisms of this regulation. In dissociated rat hippocampal neuron cultures, we used fluorescent Zn2+ sensors to rigorously define resting Zn2+ levels and stimulation-dependent intracellular Zn2+ dynamics, and we performed RNA-Seq to characterize Zn2+-dependent transcriptional effects upon stimulation. We found that relatively small changes in cytosolic Zn2+ during stimulation altered expression levels of 931 genes, and these Zn2+ dynamics induced transcription of many genes implicated in neurite expansion and synaptic growth. Additionally, while we were unable to verify the presence of synaptic Zn2+ in these cultures, we did detect the synaptic vesicle Zn2+ transporter ZnT3 and found it to be substantially upregulated by cytosolic Zn2+ increases. These results provide the first global sequencing-based examination of Zn2+-dependent changes in transcription and identify genes that may mediate Zn2+-dependent processes and functions.
Highlights
Zinc (Zn2+) is an essential trace element that is increasingly suggested to play a signaling role in a variety of different cell types
In order to rigorously define the overall Zn2+ status of dissociated hippocampal neuron cultures, we first characterized resting neuronal cytosolic and synaptic Zn2+
We sought to characterize dissociated hippocampal cultures with respect to cytosolic and synaptic Zn2+, quantify Zn2+ dynamics upon stimulation, and carry out an unbiased screen of the global changes in gene expression that result from Zn2+ dynamics to identify possible molecular players that underlie Zn2+-dependent changes in neuronal functions and processes
Summary
Zinc (Zn2+) is an essential trace element that is increasingly suggested to play a signaling role in a variety of different cell types. Transient increases in Zn2+ have been observed inside neurons after stimulation, possibly as a result of translocation of Zn2+ from the synapse or release of Zn2+ from intracellular stores[16,17,18] Both synaptic and intracellular Zn2+ signals contribute to regulation of short- and long-term plasticity in different areas of the brain[1,15,19,20], and genetic or pharmacological manipulation of hippocampal Zn2+ leads to learning and memory deficits in rodents[21,22,23]. We observed robust Zn2+-dependent differential expression of 931 genes, many of which are related to neuronal physiology and synaptic modulation To our knowledge, this is the first large-scale experiment to identify transcriptional changes of Zn2+ signals in a mammalian system, and these results can provide possible mechanistic insight into Zn2+-dependent neuronal plasticity
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