Metabotropic pathways involved in the generation of an afterdepolarization in layer V pyramidal neurons

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Metabotropic pathways involved in the generation of an afterdepolarization in layer V pyramidal neurons

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Title: Metabotropic pathways involved in the generation of an afterdepolarization in layer V pyramidal neurons
Author: Linton, Shannon Michele
Abstract: A previous study from our laboratory found that evoked spikes were followed by a long lasting afterdepolarization (ADP) in neocortical pyramidal neurons when metabotropic glutamate receptor (mGluR) agonists were present in the bathing solution. The Na+ and K+ currents involved in ADP generation depended on Ca2+ influx through voltage-gated channels and a rise in intracellular Ca2+ concentration. The present experiments were aimed at determining the mGluR subtype(s) and intracellular events underlying the ADP, as well as whether the ADP could be evoked with physiologic stimulation. Layer 5 neurons in neocortical slices from Sprague-Dawley rats (aged 14--24 days) were visualized with IR/DIC optics and recorded from using somatic whole-cell patch techniques. Drugs were introduced intracellularly via the patch pipette and in the bath. Experiments employing GDP-beta-S confirmed that the mGluR-mediated ADP is dependent upon the activation of a G-protein. Experiments using specific pharmacological mGluR agonists and antagonists determined that the mGluR-mediated ADP was due to the activation of both Group I mGluR subtypes (mGluR1 and mGluR5). Activation of Group II mGluRs had no effect on the afterpotential. Both heparin and ryanodine significantly reduced the ADP amplitude, indicating the dependence of the ADP on release of intracellular Ca2+ from both IP3-sensitive and Ca2+-sensitive stores. Biochemical studies have shown that intracellular IP3 levels evoked by activation of Group I mGluRs are significantly elevated by concurrent activation of Group II mGluRs. We found that stimulation of Group II receptors using the specific agonist DCG-IV alone did not cause an ADP, but the amplitude of the Group I (DHPG)-mediated ADP was significantly potentiated by the concurrent activation of the Group II receptors. These neurons also generate a spike-dependent, heparin-sensitive ADP when exposed to carbachol. However, no amplification of the carbachol-evoked ADP was observed with concurrent Group II activation, indicating that a specific interaction between Group I and Group II mGluRs is required for the amplification of the mGluR-dependent ADP. These experiments revealed the electrophysiological correlates in layer 5 pyramidal neurons of several mGluR-mediated events reported in biochemical studies.
Description: Thesis (Ph. D.)--University of Washington, 2000
URI: http://hdl.handle.net/1773/10554

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