Excitatory Effects of Low-Level Lead Exposure on Action Potential Firing of Pyramidal Neurons in CA1 Region of Rat Hippocampal Slices

J Neurosci Res. 2008 Dec;86(16):3665-73. doi: 10.1002/jnr.21804.

Abstract

Lead is putatively regarded as an environmental neurotoxicant. Long-term low-level lead exposure causes cognitive deficits, but the mechanism remains to be elucidated. In the present study, the excitatory effects of low-level lead exposure on action potential (AP) firing of pyramidal neurons in CA1 region of rat hippocampal slices and the pathway through which lead induced these effects were studied with conventional whole-cell recording. Low-level lead (0.5 and 5 microM) exposure did not significantly change either voltage threshold or amplitude, duration, rise time, or rising velocity of single AP; conversely, 5 microM lead exposure significantly increased AP firing rates and reduced spike frequency adaptation. These excitatory effects of 5 microM lead were blocked by mibefradil, a selective blocker of T-type voltage-dependent calcium channels (VDCC), but not by verapamil and omega-conotoxin, selective blockers of L-type and N-type VDCC, respectively. Five micromolar lead could not 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, but not by thapsigargin, an inhibitor of endoplasmic reticulum calcium uptake. These results provide 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, T-Type / drug effects
  • Calcium Channels, T-Type / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Dose-Response Relationship, Drug
  • Hazardous Substances / toxicity
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
  • Lead / toxicity*
  • Lead Poisoning, Nervous System / physiopathology*
  • Male
  • Mibefradil / pharmacology
  • Neurotoxins / toxicity*
  • Organ Culture Techniques
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Wistar
  • Ryanodine Receptor Calcium Release Channel / drug effects

Substances

  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Hazardous Substances
  • Inositol 1,4,5-Trisphosphate Receptors
  • Neurotoxins
  • Ryanodine Receptor Calcium Release Channel
  • Mibefradil
  • Lead