title: The auxiliary subunit KChIP2 is an essential regulator of homeostatic excitability.
abstract: BACKGROUND
  The necessity for, or redundancy of, distinctive KChIP proteins is not known.
  
  
  RESULTS
  Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons.
  
  
  CONCLUSIONS
  KChIP2 is essential for homeostasis in hippocampal neurons.
  
  
  CONCLUSIONS
  Mutations in K(A) channel auxiliary subunits may be loci for epilepsy. The somatodendritic IA (A-type) K(+) current underlies neuronal excitability, and loss of IA has been associated with the development of epilepsy. Whether any one of the four auxiliary potassium channel interacting proteins (KChIPs), KChIP1-KChIP4, in specific neuronal populations is critical for IA is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for IA regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V½ for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of IA, hippocampal neurons from Kchip2(-/-) mice showed increased excitability. WT cultured neurons fired only occasional single action potentials, but the average spontaneous firing rate (spikes/s) was almost 10-fold greater in Kchip2(-/-) neurons. In slice preparations, spontaneous firing was detected in CA1 pyramidal neurons from Kchip2(-/-) mice but not from WT. Additionally, when seizures were induced by kindling, the number of stimulations required to evoke an initial class 4 or 5 seizure was decreased, and the average duration of electrographic seizures was longer in Kchip2(-/-) mice compared with WT controls. Together, these data demonstrate that the KChIP2 is essential for physiologic IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University, Medical Center, Durham, NC 27710, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Xiao Ping
authors.initials: XP
authors.lastname: He
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Roger D
authors.initials: RD
authors.lastname: Madison
authors.forename: Scott D
authors.initials: SD
authors.lastname: Moore
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000200:Action Potentials; D000679:Amygdala / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials; D006706:Homeostasis; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D007696:Kindling, Neurologic; D051605:Kv Channel-Interacting Proteins / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D012640:Seizures
chemical_list: C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D021122:Protein Subunits
keywords: A-type potassium channel modulation; Electrophysiology; Epilepsy; Ion channels; KChIP2; Neurological diseases; Neurons; hippocampus; homeostasis; neuronal excitability
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