Elsevier

Neuroscience

Volume 62, Issue 3, October 1994, Pages 813-828
Neuroscience

Impairment of gabaa receptor function byn-methyl-d-aspartate-mediated calcium influx in isolated ca1 pyramidal cells

https://doi.org/10.1016/0306-4522(94)90479-0Get rights and content

Abstract

Mechanisms of regulation of GABAA receptor function by intracellular calcium ([Ca2+]i) were examined in cell somata and apical dendrites of pyramidal cells, acutely dissociated from the CA1 hippocampal subfield of adult guinea-pigs. GABAA receptor-mediated currents were measured by whole-cell clamp recordings.N-methyl-d-aspartate receptor-mediated currents were used as conditioning source of calcium influx. Peak amplitudes of somatic GABAA whole-cell currents were reduced to about 15% of control values when net inward charge accumulation byN-methyl-d-aspartate currents reached 1.85 nC. A similar decline of GABAA currents was observed in dendritic recordings. TheN-methyl-d-as partate-mediated reduction of somatic and dendritic GABAA currents was accompanied by a well correlated decrease in peak and chord conductances. Pharmacological blockade ofN-methyl-d-aspartate currents by 2-amino-5-phosphonopentanoic acid prevented theN-methyl-d-aspartate-mediated suppression of GABAA responses. TheN-methyl-d-aspartate effect was mediated by the calcium component ofN-methyl-d-aspartate receptor-mediated currents as demonstrated by a lack of effect in the absence of extracellular calcium and fasterN-methyl-d-aspartate-mediated suppression of GABAA responses in lower intracellular1,2-bis(2-aminophenoxy)ethane-N,N,N′,N″-tetra-acetate.N-methyl-d-aspartate-mediated suppression of GABAA currents was significantly less expressed when intracellular ATP was replaced by its analog adenosine5′-O-(3-thiotriphosphate) and when the specific phosphatase 2B inhibitor cypermethrin was added intracellularly. The reduction of GABAA responses persisted after cessation ofN-methyl-d-aspartate-mediated calcium influx, indicating a long-term action ofN-methyl-d-aspartate on GABAA responses. Voltage-activated calcium currents did not affect GABAA responses under the experimental conditions applied.

In conclusion, the data presented show that calcium influxes throughN-methyl-d-aspartate receptor channels result in long-term suppression of GABAA receptor function in CA1 pyramidal cells. Intracellular mechanisms ofN-methyl-d-aspartate-mediated reduction of GABAA conductances involve activation of phosphatase 2B and consecutive dephosphorylation of the GABAA receptor or a closely associated GABAA receptor-regulating enzyme. Possible mechanisms of such a distinctN-methyl-d-aspartate-dependent calcium signalling pathway in the dephosphorylation-dependent suppression or GABAA receptor function are discussed.

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