Intracellular Zn(2+) transients modulate global gene expression in dissociated rat hippocampal neurons

Zinc (Zn(2+)) 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 Zn(2+) 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 Zn(2+) sensors to rigorously define resting Zn(2+) levels and stimulation-dependent intracellular Zn(2+) dynamics, and we performed RNA-Seq to characterize Zn(2+)-dependent transcriptional effects upon stimulation. We found that relatively small changes in cytosolic Zn(2+) during stimulation altered expression levels of 931 genes, and these Zn(2+) dynamics induced transcription of many genes implicated in neurite expansion and synaptic growth. Additionally, while we were unable to verify the presence of synaptic Zn(2+) in these cultures, we did detect the synaptic vesicle Zn(2+) transporter ZnT3 and found it to be substantially upregulated by cytosolic Zn(2+) increases. These results provide the first global sequencing-based examination of Zn(2+)-dependent changes in transcription and identify genes that may mediate Zn(2+)-dependent processes and functions.