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Reduced Mg2+ blockade of synaptically activated N-methyl-D-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus.
Neuroscience. 1999; 88(3):727-39.N

Abstract

Unilateral kainic acid lesion in the hippocampus caused a long-term change in the balance between excitatory and inhibitory drive onto CA1 pyramidal cells, making these cells hyperexcitable several weeks post-lesion. In this study, we have shown an enhanced N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission together with a reduced GABA(A) receptor-mediated inhibition in CA1 pyramidal cells one-week post kainic acid lesion. In these cells, pharmacologically isolated N-methyl-D-aspartate receptor-mediated whole-cell excitatory postsynaptic currents were significantly larger at negative holding potentials, and the voltage-dependence of N-methyl-D-aspartate receptor channels was shifted in the hyperpolarizing direction. The plot of relative conductance (g/gMax) shifted significantly (P<0.01) to more negative holding potentials by 19 mV (-28+/-4 mV in control slices and -47+/-4 mV in kainic acid slices) at the half maximal conductance point (g/gMax =0.5). This shift gives a larger N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission at resting membrane potentials (around -60 mV). The shifted voltage dependence is highly sensitive to extracellular Mg2+ ions. Moderate increases in [Mg2+]o from 1 mM to 2.6 mM more than compensated for the negative shift and effectively suppressed the population epileptiform bursting activity. Fitting the voltage dependence to an ionic block model revealed a higher dissociation constant of N-methyl-D-aspartate receptor channels for Mg2+ in kainic acid-lesioned slices (52 mM at 0 mV; 330 microM at -60 mV) than in control slices (7.7 mM at 0 mV; 93 microM at -60 mV). While a simple single site model adequately fitted the control data for [Mg2+]o at 1 mM and 2.6 mM, no consistent model of this form was found for the kainic acid-lesioned slices. These results revealed changed properties of N-methyl-D-aspartate receptor channels in the kainic acid-lesioned model of epilepsy. The reduced Mg2+ blockade of N-methyl-D-aspartate receptor channels contributed significantly to the epileptiform bursting activity.

Authors+Show Affiliations

Neuroscience Research Group, School of Biological Sciences, University of Southampton, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10363813

Citation

Chen, Y, et al. "Reduced Mg2+ Blockade of Synaptically Activated N-methyl-D-aspartate Receptor-channels in CA1 Pyramidal Neurons in Kainic Acid-lesioned Rat Hippocampus." Neuroscience, vol. 88, no. 3, 1999, pp. 727-39.
Chen Y, Chad JE, Cannon RC, et al. Reduced Mg2+ blockade of synaptically activated N-methyl-D-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus. Neuroscience. 1999;88(3):727-39.
Chen, Y., Chad, J. E., Cannon, R. C., & Wheal, H. V. (1999). Reduced Mg2+ blockade of synaptically activated N-methyl-D-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus. Neuroscience, 88(3), 727-39.
Chen Y, et al. Reduced Mg2+ Blockade of Synaptically Activated N-methyl-D-aspartate Receptor-channels in CA1 Pyramidal Neurons in Kainic Acid-lesioned Rat Hippocampus. Neuroscience. 1999;88(3):727-39. PubMed PMID: 10363813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduced Mg2+ blockade of synaptically activated N-methyl-D-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus. AU - Chen,Y, AU - Chad,J E, AU - Cannon,R C, AU - Wheal,H V, PY - 1999/6/11/pubmed PY - 1999/6/11/medline PY - 1999/6/11/entrez SP - 727 EP - 39 JF - Neuroscience JO - Neuroscience VL - 88 IS - 3 N2 - Unilateral kainic acid lesion in the hippocampus caused a long-term change in the balance between excitatory and inhibitory drive onto CA1 pyramidal cells, making these cells hyperexcitable several weeks post-lesion. In this study, we have shown an enhanced N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission together with a reduced GABA(A) receptor-mediated inhibition in CA1 pyramidal cells one-week post kainic acid lesion. In these cells, pharmacologically isolated N-methyl-D-aspartate receptor-mediated whole-cell excitatory postsynaptic currents were significantly larger at negative holding potentials, and the voltage-dependence of N-methyl-D-aspartate receptor channels was shifted in the hyperpolarizing direction. The plot of relative conductance (g/gMax) shifted significantly (P<0.01) to more negative holding potentials by 19 mV (-28+/-4 mV in control slices and -47+/-4 mV in kainic acid slices) at the half maximal conductance point (g/gMax =0.5). This shift gives a larger N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission at resting membrane potentials (around -60 mV). The shifted voltage dependence is highly sensitive to extracellular Mg2+ ions. Moderate increases in [Mg2+]o from 1 mM to 2.6 mM more than compensated for the negative shift and effectively suppressed the population epileptiform bursting activity. Fitting the voltage dependence to an ionic block model revealed a higher dissociation constant of N-methyl-D-aspartate receptor channels for Mg2+ in kainic acid-lesioned slices (52 mM at 0 mV; 330 microM at -60 mV) than in control slices (7.7 mM at 0 mV; 93 microM at -60 mV). While a simple single site model adequately fitted the control data for [Mg2+]o at 1 mM and 2.6 mM, no consistent model of this form was found for the kainic acid-lesioned slices. These results revealed changed properties of N-methyl-D-aspartate receptor channels in the kainic acid-lesioned model of epilepsy. The reduced Mg2+ blockade of N-methyl-D-aspartate receptor channels contributed significantly to the epileptiform bursting activity. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/10363813/Reduced_Mg2+_blockade_of_synaptically_activated_N_methyl_D_aspartate_receptor_channels_in_CA1_pyramidal_neurons_in_kainic_acid_lesioned_rat_hippocampus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S030645229800253X DB - PRIME DP - Unbound Medicine ER -