Reduced Mg2+ blockade of synaptically activated N-methyl-D- aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus
Chen, Y., Chad, J.E., Cannon, R.C. and 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), 727-739. (doi:10.1016/S0306-4522(98)00253-X).
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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 GABAA receptor-mediated inhibition in CA1 pyramidal cells one-week post kainic acid lesion. In these cells, pharmacologically isolated N-methyl-Image -aspartate receptor-mediated whole-cell excitatory postsynaptic currents were significantly larger at negative holding potentials, and the voltage-dependence of N-methyl-Image -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-Image -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-Image -aspartate receptor channels for Mg2+ in kainic acid-lesioned slices (52 mM at 0 mV; 330 μM at −60 mV) than in control slices (7.7 mM at 0 mV; 93 μM 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-Image -aspartate receptor channels in the kainic acid-lesioned model of epilepsy. The reduced Mg2+ blockade of N-methyl-Image -aspartate receptor channels contributed significantly to the epileptiform bursting activity.
|Keywords:||NMDA, AMPA, GABA, epilepsy, in vitro, EPSC|
|Subjects:||Q Science > QL Zoology
Q Science > QD Chemistry
Q Science > QR Microbiology
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||21 Aug 2008|
|Last Modified:||06 Aug 2015 02:45|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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