title: Targeted deletion of Kcne2 impairs HCN channel function in mouse thalamocortical circuits.
abstract: BACKGROUND
  Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, I(h), which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown.
  
  
  RESULTS
  We investigated the effects of Kcne2 gene deletion on I(h) properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from Kcne2(+/+) and Kcne2(-/-) mice. Kcne2 deletion shifted the voltage-dependence of I(h) activation to more hyperpolarized potentials, slowed gating kinetics, and decreased I(h) density. Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. Kcne2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; such augmented excitability did not result from changes in glutamate release machinery since miniature EPSC frequency was unaltered in Kcne2(-/-) neurons.
  
  
  CONCLUSIONS
  Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Shui-Wang
authors.initials: SW
authors.lastname: Ying
authors.forename: Vikram A
authors.initials: VA
authors.lastname: Kanda
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.forename: Kerry
authors.initials: K
authors.lastname: Purtell
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
authors.forename: Peter A
authors.initials: PA
authors.lastname: Goldstein
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D005971:Glutamates / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D005971:Glutamates; C578666:Hcn1 protein, mouse; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; C489620:Kcne2 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011743:Pyrimidines; C082246:ICI D2788; D015761:4-Aminopyridine