Insight into glutamate excitotoxicity from synaptic zinc homeostasis

Abstract

Zinc is released from glutamatergic (zincergic) neuron terminals in the hippocampus, followed by the increase in Zn(2+) concentration in the intracellular (cytosol) compartment, as well as that in the extracellular compartment. The increase in Zn(2+) concentration in the intracellular compartment during synaptic excitation is mainly due to Zn(2+) influx through calcium-permeable channels and serves as Zn(2+) signaling as well as the case in the extracellular compartment. Synaptic Zn(2+) homeostasis is important for glutamate signaling and altered under numerous pathological processes such as Alzheimer's disease. Synaptic Zn(2+) homeostasis might be altered in old age, and this alteration might be involved in the pathogenesis and progression of Alzheimer's disease; Zinc may play as a key-mediating factor in the pathophysiology of Alzheimer's disease. This paper summarizes the role of Zn(2+) signaling in glutamate excitotoxicity, which is involved in Alzheimer's disease, to understand the significance of synaptic Zn(2+) homeostasis in the pathophysiology of Alzheimer's disease.

Figure 1

Changes in zinc signals in the extracellular and intracellular compartments in the hippocampal CA1 during tetanic stimulation. (a) Hippocampal illustration and CA1 image with ZnAF-2. (b) High-frequency stimulation (HSF, 200 Hz, 1 s) was delivered to the Schaffer collaterals in hippocampal slices stained with ZnAF-2 or ZnAF-2DA. The circle (around 10 μm in diameter) shown in Figure 1(a) is a representative example of the region of interest. The data represents the changed rate (%) in fluorescent signals to the basal fluorescent signal before the stimulation, which is expressed as 100%. The red bar indicates the period of electrical stimulation. (c) Tetanic stimulation (200 Hz, 1 s) was delivered to the Schaffer collaterals in hippocampal slices immersed in ACSF (control), 1 mM CaEDTA in ACSF, or 10 μM CNQX in ACSF. The data represents the changed rate (%) in fluorescent signal during tetanic stimulation to the basal fluorescent signal before the stimulation, which is expressed as 100%. ***P < .001, versus the basal level before the stimulation; ^##P < .01, ^###P < .001, versus the control (stimulated in ACSF). This data is cited from the paper published by Journal of Neuroscience Research, 2007 [35].

Figure 2

Zn²⁺ signaling and glutamate excitotoxicity. Zinc released from zincergic neuron terminals is immediately taken up into presynaptic and postsynaptic neurons through calcium-permeable channels (CaC and GluR). In presynaptic neurons, zinc negatively modulates exocytosis. The negative modulation by zinc may protectively serve for postsynaptic neurons under pathological conditions that are linked with glutamate excitotoxicity.

Figure 3

Histochemically reactive zinc level and its relation to the pathogenesis of Alzheimer's disease. Zinc deficiency can reduce histochemically reactive zinc levels, which are estimated to be susceptible to aging. Zinc deficiency, as well as aging, seems to be a risk factor for Alzheimer's disease.