Effects Of Lead Exposure In Different Ways On Excitability And Sodium Channels Of Pyramidal Neurons In Rat Hippocampus

Lead is putatively regarded as an environmental neurotoxicant. Long term low level lead exposure can cause cognitive deficits. But, its mechanism remained to be elucidated. In the present study, effects of lead exposure in different ways on the excitability and some excitability-related voltage-gated ion channels of pyramidal neurons in CA1 region of rat hippocampal slices and the pathway through which lead cause these effects were studied with conventional whole- cell recording.The results of acute lead exposure experiments showed that low-level lead (0.5 and 5μM) exposure didn't significantly change either voltage threshold or the amplitude, duration, rise time and rising velocity of single action potential (AP); conversely 5μM lead exposure significantly increased AP firing rates, and reduced spike frequency adaptation. These excitatory effects of 5μM lead were blocked by mibefradil, a selective blocker of T-type voltage dependent calcium channels (VDCC), but not by verapamil orω-conotoxin, selective blocker of L- type and N- type VDCC respectively. 5μM lead couldn't change the excitability of pyramidal neurons when slices were perfused with calcium-free ACSF. In addition, the effects were abolished by inhibitors of two intracellular calcium release channels: 2-APB, an inhibitor of inositol trisphosphate receptors, and dantrolene, an inhibitor of ryanodine receptors, respectively, but not by thapsigargin, an inhibitor of endoplasmic reticulum calcium uptake. These results present evidence for excitatory neurotoxicity of low-level lead exposure, contribution of T-type VDCC in the entrance of lead into neurons, and a possible involvement of calcium flux alteration during APs in this excitatory neurotoxicity.The results of developmental chronic lead exposure experiments showed that developmental lead exposure increased the activation threshold and the voltage at which the maximum I_Na current was evoked, caused positive shifts of I_Na steady-state activation curve, and enlarged I_Na tail-currents; Pb²⁺ delayed the activation of I_Na in a voltage-dependent manner, prolonged the time course of the fast inactivation of sodium channels; Pb²⁺ induced a right shift of the steady-state inactivation curve, accelerated the activity-dependent attenuation of I_Na, but made no significant effects on the time course of the recovery of I_Na from inactivation and the fraction of inactivated channels. In addition, the co-treatment withα-tocopherol (VE), an effective antioxidant and free radical scavenger, completely prevented the aforementioned changes on I_Na. So, the process was considered related to the participating of lead in lipid peroxidation reaction, which has been reported to change the conformation and biophysical functions of membrane proteins.