Chronic Zinc Exposure Decreases The Surface Expression Of NR2A-containing NMDA Receptors In Cultured Hippocampal Neurons

The brain has considerable zinc content with the highest concentration in the hippocampus, amygdala and cortex. In neurons, zinc binds tightly to numerous enzymes, structural proteins and transcription factors. Zinc is also buffered by the metal lothioneins and sequestered in mitochondria. In glutamatergic neurons, zinc is present at up to millimolar concentration in presynaptic vesicles and is released from these neurons with glutamate and taken up by presynaptic axon terminals, postsynaptic neurons and neighbouring astrocytes. All these sources of zinc contribute to the dynamic balance of zinc, which is critical for its functions in neurons. Increasing evidence indicates that zinc imbalance plays important roles in the pathophysiologic progress。The N-methyl-D-aspartate receptor (NMDAR) is the predominant molecule for controlling synaptic plasticity and learning and memory in the central nervous system. Recent findings show that AD mice suffer the defects of NMDAR-mediated long-term potentiation (LTP) and cognitive loss, but the mechanism is not clear. It is well-known that zinc acutely and allosterically regulates the activity of NMDARs. Zinc suppresses the NR2A-containing NMDARs by either high-affinity (5-300nM) and voltage-independent inhibition or low-affinity (45-79μM) and voltage-dependent inhibition. Zinc also inhibits the NR2B-containing NMDARs at the micromolar level and in a voltage-independent manner. Zinc is co-released with glutamate upon synaptic activation and enters postsynaptic neurons, producing transient increases of intracellular zinc. Therefore, zinc plays important roles in the maintainece of cortical excitability and NMDAR-mediated synaptic plasticity. In addition, several studies demonstrated that zinc binds to protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ). These findings imply that intracellular zinc may be an essential element in modulating NMDAR activities.Inappropriate activity of NMDARs has been implicated in the aetiology of neurodegenerative diseases. Researches into AD pathology have identified the NMDAR-mediated neurotransmission as a potential target for drug discovery and development. A phased accumulation of zinc is also shown in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). However, how the zinc imbalance links to NMDAR dysfunction in neurodegenerative diseases is unknown. The present work was undertaken to remedy this omission. We chronically treated the cultured hippocampal neurons with100nM zinc. Results derived from immunostaining and electrophysiology demonstrated that this chronic zinc exposure specifically decreased the surface expression of NR2A-containing NMDARs and the currents mediated by them. The mechanisms of these zinc effects included the disruption of the physical association of the NR2A-PSD95-Src complex. These data indicate a novel action of zinc on NMDARs that may be involved in the defects of plasticity and memory in AD.