TY - JOUR
T1 - Increased Kv1 channel expression may contribute to decreased sipsc frequency following chronic inhibition of NR2B-containing NMDAR
AU - He, Shuijin
AU - Shao, Li Rong
AU - Rittase, W. Bradley
AU - Bausch, Suzanne B.
N1 - Funding Information:
We thank Dr Yves Auberson for his kind gift of NVP-AAM077, Dr Ed Cooper for helpful discussions, and Dr Zygmunt Galdzicki for critical reading of an earlier version of the manuscript. Work was supported by the Congressionally Directed Medical Research Programs award W81XWH-04-1-0065/PR030035 and National Institute of Neurological Disorders and Stroke grant NS045964. The monoclonal antibodies against Kv1.2, 1.3, and 1.6 were developed and obtained from the UC Davis/NINDS/NIMH NeuroMab Facility, supported by the NIH grant U24NS050606 and maintained by the Department of Pharmacology, School of Medicine, University of California, Davis, CA. All treatment of animals complied with National Institutes of Health, Department of Defense and institutional guidelines.
PY - 2012/5
Y1 - 2012/5
N2 - Numerous studies have documented the effects of chronic N-methyl-D-aspartate receptor (NMDAR) blockade on excitatory circuits, but the effects on inhibitory circuitry are not well studied. NR2A-and NR2B-containing NMDARs play differential roles in physiological processes, but the consequences of chronic NR2A-or NR2B-containing NMDAR inhibition on glutamatergic and GABAergic neurotransmission are unknown. We investigated altered GABAergic neurotransmission in dentate granule cells and interneurons following chronic treatment with the NR2B-selective antagonist, Ro25,6981, the NR2A-prefering antagonist, NVP-AAM077, or the non-subunit-selective NMDAR antagonist, D-APV, in organotypic hippocampal slice cultures. Electrophysiological recordings revealed large reductions in spontaneous inhibitory postsynaptic current (sIPSC) frequency in both granule cells and interneurons following chronic Ro25,6981 treatment, which was associated with minimally altered sIPSC amplitude, miniature inhibitory postsynaptic current (mIPSC) frequency, and mIPSC amplitude, suggesting diminished action potential-dependent GABA release. Chronic NVP-AAM077 or D-APV treatment had little effect on these measures. Reduced sIPSC frequency did not arise from downregulated GABA A R, altered excitatory or inhibitory drive to interneurons, altered interneuron membrane properties, increased failure rate, decreased action potential-dependent release probability, or mGluR/GABA B receptor modulation of GABA release. However, chronic Ro25,6981-mediated reductions in sIPSC frequency were occluded by the K + channel blockers, dendrotoxin, margatoxin, and agitoxin, but not dendrotoxin-K or XE991. Immunohistochemistry also showed increased Kv1.2, Kv1.3, and Kv1.6 in the dentate molecular layer following chronic Ro25,6981 treatment. Our findings suggest that increased Kv1 channel expression/function contributed to diminished action potential-dependent GABA release following chronic NR2B-containing NMDAR inhibition and that these Kv1 channels may be heteromeric complexes containing Kv1.2, Kv1.3, and Kv1.6.
AB - Numerous studies have documented the effects of chronic N-methyl-D-aspartate receptor (NMDAR) blockade on excitatory circuits, but the effects on inhibitory circuitry are not well studied. NR2A-and NR2B-containing NMDARs play differential roles in physiological processes, but the consequences of chronic NR2A-or NR2B-containing NMDAR inhibition on glutamatergic and GABAergic neurotransmission are unknown. We investigated altered GABAergic neurotransmission in dentate granule cells and interneurons following chronic treatment with the NR2B-selective antagonist, Ro25,6981, the NR2A-prefering antagonist, NVP-AAM077, or the non-subunit-selective NMDAR antagonist, D-APV, in organotypic hippocampal slice cultures. Electrophysiological recordings revealed large reductions in spontaneous inhibitory postsynaptic current (sIPSC) frequency in both granule cells and interneurons following chronic Ro25,6981 treatment, which was associated with minimally altered sIPSC amplitude, miniature inhibitory postsynaptic current (mIPSC) frequency, and mIPSC amplitude, suggesting diminished action potential-dependent GABA release. Chronic NVP-AAM077 or D-APV treatment had little effect on these measures. Reduced sIPSC frequency did not arise from downregulated GABA A R, altered excitatory or inhibitory drive to interneurons, altered interneuron membrane properties, increased failure rate, decreased action potential-dependent release probability, or mGluR/GABA B receptor modulation of GABA release. However, chronic Ro25,6981-mediated reductions in sIPSC frequency were occluded by the K + channel blockers, dendrotoxin, margatoxin, and agitoxin, but not dendrotoxin-K or XE991. Immunohistochemistry also showed increased Kv1.2, Kv1.3, and Kv1.6 in the dentate molecular layer following chronic Ro25,6981 treatment. Our findings suggest that increased Kv1 channel expression/function contributed to diminished action potential-dependent GABA release following chronic NR2B-containing NMDAR inhibition and that these Kv1 channels may be heteromeric complexes containing Kv1.2, Kv1.3, and Kv1.6.
KW - dentate granule cell
KW - hippocampus
KW - interneuron
KW - plasticity
KW - potassium channel
KW - slice culture
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U2 - 10.1038/npp.2011.320
DO - 10.1038/npp.2011.320
M3 - Article
C2 - 22218089
AN - SCOPUS:84859749014
SN - 0893-133X
VL - 37
SP - 1338
EP - 1356
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 6
ER -