Intracellular Zn²⁺ signaling in the dentate gyrus is required for object recognition memory

Abstract

The role of perforant pathway-dentate granule cell synapses in cognitive behavior was examined focusing on synaptic Zn(2+) signaling in the dentate gyrus. Object recognition memory was transiently impaired when extracellular Zn(2+) levels were decreased by injection of clioquinol and N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendediamine. To pursue the effect of the loss and/or blockade of Zn(2+) signaling in dentate granule cells, ZnAF-2DA (100 pmol, 0.1 mM/1 µl), an intracellular Zn(2+) chelator, was locally injected into the dentate molecular layer of rats. ZnAF-2DA injection, which was estimated to chelate intracellular Zn(2+) signaling only in the dentate gyrus, affected object recognition memory 1 h after training without affecting intracellular Ca(2+) signaling in the dentate molecular layer. In vivo dentate gyrus long-term potentiation (LTP) was affected under the local perfusion of the recording region (the dentate granule cell layer) with 0.1 mM ZnAF-2DA, but not with 1-10 mM CaEDTA, an extracellular Zn(2+) chelator, suggesting that the blockade of intracellular Zn(2+) signaling in dentate granule cells affects dentate gyrus LTP. The present study demonstrates that intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory, probably via dentate gyrus LTP expression.

Supplementation with zinc in rats enhances memory and reverses an age-dependent increase in plasma copper

“…The role of zinc in mnemonic processing has been previously explored [85–88], but this is the first report we are aware of showing an effect of zinc supplementation to enhance memory above baseline.…”

Excess influx of Zn 2+ into dentate granule cells affects object recognition memory via attenuated LTP

“…The attenuation of LTP may be linked to the impairment of object recognition (Takeda et al, 2014). Training of the object recognition test was performed 1 h after KCl injection and the test was performed 1 h after the training.…”

“…Furthermore, high K + -induced memory deficit was not observed when the memory test was performed 24 h after KCl injection, indicating that the effect of excess influx of Zn 2+ on memory deficit is transient in the present experiment condition. In contrast, blockage of intracellular Zn 2+ signaling with a zinc chelator in the dentate gyrus affects object recognition via attenuation of LTP (Takeda et al, 2014) and also erases recognition memory via impairment of maintained LTP (Tamano et al, 2015). It is likely that both extracellular and intracellular Zn 2+ homeostasis is strictly regulated for plastic changes in synapses in the dentate gyrus where is scarcely innervated by zincergic neurons.…”

“…The physiological significance of extracellular Zn 2+ dynamics has not been reported in the dentate gyrus. We have reported that intracellular Zn 2+ signaling in dentate granule cells is required for object recognition memory, probably via dentate gyrus LTP expression, and that extracellular Zn 2+ signaling is nonessential for dentate gyrus LTP induction (Takeda et al, 2010(Takeda et al, , 2014. On the other hand, it is possible that extracellular Zn 2+ is involved in synaptic dysfunctions, which are linked with cognitive decline, because the influx of Zn 2+ into postsynaptic neurons is likely to occur via calcium channels even during non-zincergic synapse excitation.…”

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β_1–42 Neurotoxicity Linked with Modified Extracellular Zn²⁺ Dynamics?

“…41) LTP maintenance underlies memory retention. The mechanism maintaining medial perforant pathway LTP also requires intracellular Zn 2+ signaling in dentate granule cells, which is involved in the formation of F-actin, and retains space recognition memory.…”