Increased Kv1 channel expression may contribute to decreased sIPSC frequency following chronic inhibition of NR2B-containing NMDAR.
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.
Department of Pharmacology, Uniformed Services University School of Medicine, Bethesda, MD, USA.
Shuijin
S
He
Li-Rong
LR
Shao
W Bradley
WB
Rittase
Suzanne B
SB
Bausch
D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism*; D026941:Sodium Channel Blockers; D018709:Statistics, Nonparametric; D013779:Tetrodotoxin / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D051637:Shaker Superfamily of Potassium Channels; D026941:Sodium Channel Blockers; C070614:neurobiotin; D013779:Tetrodotoxin; D001710:Biotin