Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice.
Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild-type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (I(h)) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, I(h) is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABA(A) current in these cells that could be attributed to selective upregulation of GABA(A) alpha5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished I(h), baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knock-out mice; however, blocking tonic GABA(A) currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knock-out mice than in those cells from wild-type mice. Increasing tonic GABA(A) receptor conductance in the context of reduced I(h), using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knock-out mice. These data indicate that upregulation of alpha5 subunit-mediated GABA(A) receptor tonic current compensates quantitatively for loss of dendritic I(h) in cortical pyramidal neurons from HCN1 knock-out mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo.
Chen
Xiangdong
X
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
Shu
Shaofang
S
Schwartz
Lauren C
LC
Sun
Chengsan
C
Kapur
Jaideep
J
Bayliss
Douglas A
DA
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000172:deficiency* / Q000502:physiology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000502:physiology*; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D021122:Protein Subunits; D011724:Pyridazines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D026941:Sodium Channel Blockers; C082246:ICI D2788; D003900:Desoxycorticosterone; D013779:Tetrodotoxin; C009413:tetrahydrodeoxycorticosterone; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; C049853:gabazine; D014633:Valine; D001640:Bicuculline