Effects Of Cadmium On Potassium Channels, Glycine Receptor And AMPA Receptor-mediated Excitatory Synaptic Transmission In Rat Hippocampal CA1 Area

Cadmium (Cd²⁺), a common environmental pollutant, is a nonphysiological metal potentially toxic to human. Cadmium exposure causes a variety of impairments to kidney, lung, gastrointestinal tract, bone and the central nervous system (CNS). In the CNS, especially during development, chronic cadmium exposure causes biochemical and morphological changes of the brain and results in cognitive function disabilities. In this study, using electrophysiological methods, we investigated the neurotoxic mechanisms of Cd²⁺ in hippocampus in the following directions.1) With whole-cell patch-clamp recording in rat hippocampal slices, we examined the effects of Cd²⁺ on AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor-mediated synaptic transmission and short-term synaptic plasticity in hippocampal CA1 area.The subtype excitatory amino acid AMPA receptors play a central role in fast synaptic transmission and plasticity at most CNS excitatory synapses. Changes to the strength of AMPA receptor-mediated synaptic transmission are involved with normal physiological brain functions, including learning and memory, as well as with many neuropathological disorders. Cd²⁺ significantly inhibited the peak amplitude of evoked EPSCs (eEPSCs) in a concentration-dependent manner and enhanced the short-term synaptic plasticity including paired-pulse facilitation and frequency facilitation. Cd²⁺ also decreased the frequency and amplitude of spontaneous EPSCs (sEPSCs) but had no effect on those of miniature EPSCs (mEPSCs). These effects of Cd²⁺ may involve a presynaptic mechanism of blockade of action potential-sensitive, calcium-dependent release of glutamate. In addition, Cd²⁺ prolonged the decay time of both sEPSCs and mEPSCs, which suggested a postsynaptic action site of Cd²⁺. This study demonstrates that Cd²⁺ impairs the Schaffer collateral-commissural-CA1 glutamatergic synaptic transmission and short-term plasticity in rat hippocampal slices, which may be a possible mechanism underlying the Cd²⁺-induced neurotoxic effects.2) The effects of Cd²⁺ on the transient outward potassium current (I_A) and delayed rectifier potassium current (I_K) were investigated in acutely dissociated rat hippocampal CA1 neurons using the whole-cell patch-clamp technique.In nervous system, Voltage-gated potassium currents play crucial roles in modifying neuronal cellular and network excitability, the regulation of potassium channels would make neurons display aberrant firing properties and abnormal neuronal discharge. The results showed that Cd²⁺ inhibited the amplitudes of I_A and I_Kin a reversible and concentration-dependent manner, with IC₅₀ values of 546±59 and 749±53μM, and the inhibitory effect of Cd²⁺ was voltage-dependent. Cd²⁺ significantly shifted the steady-state activation and inactivation curve of I_A to more positive potentials. In contrast, Cd²⁺ caused a relatively less but still significant positive shift in the activation of I_K without effect on the inactivation curve. Cd²⁺ significantly slowed the recovery from inactivation of I_K but had no effect on the recovery time course of I_A. The results suggested that the modulation of I_A and I_K was most likely mediated by the interaction of Cd²⁺ with a specific site on the potassium channel protein, rather than by screening of bulk surface negative charge. The effects of Cd²⁺ on the voltage-gated potassium currents may be a possible contributing mechanism for the Cd²⁺-induced neurotoxic damage. In addition, the effects of Cd²⁺ on the potassium currents at concentrations that overlap with its effects on calcium currents raise the concerns about its use in pharmacological or physiological studies.3) The effects of Cd²⁺ on glycine-induced Cl^- current (I_Gly) were investigated in acutely dissociated rat hippocampal CA1 neurons using the whole-cell patch-clamp technique in this study.In hippocampus, GlyR may participate in an inhibitory mechanism by affecting somatical firing and synaptic transmission, the modulation of GlyR may affect hippocampal information processing. We found that Cd²⁺ reversibly and concentration-dependently reduced the amplitudes of I_Gly, with an IC₅₀ of 1.27 mM and Hill coefficient of 0.45. The depression of I_Gly by Cd²⁺ was independent of membrane voltage between -60mV and +40mV and didn't involve a shift in the reversal potential of the current. A noncompetitive inhibition was suggested by a double reciprocal plot of the effects of Cd²⁺ on the concentration-response curve of the I_Gly. Since intracellular dialysis with 3 mM Cd²⁺ failed to modify I_Gly, it was suggested that the site of action of Cd²⁺ is extracellular. The suppression of I_Gly by Zn²⁺ was unaffected by 3 mM Cd²⁺, which indicated that Zn²⁺ and Cd²⁺ bind to independent sites on glycine receptor. The results show that Cd²⁺ decreases I_Gly in acutely dissociated rat hippocampal neurons and the present study may be helpful to understand the mechanisms of cadmium-induced neurotoxicity.