Altered Aβ formation and long-term potentiation in a calsenilin knock-out

Christina Lilliehook, Ozlem Bozdagi, Jun Yao, Manuel Gomez-Ramirez, Nikhat F. Zaidi, Wilma Wasco, Sam Gandy, Anthony C. Santucci, Vahram Haroutunian, George W. Huntley, Joseph D. Buxbaum

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a β-subunit of Kv4 channels and could, thus, be a multifunctional protein. To study these functions of calsenilin in vivo and to determine the neuroanatomical expression pattern of calsenilin, we generated mice with a disruption of the calsenilin gene by the targeted insertion of the β-galactosidase gene. We found that calsenilin expression (as represented by β-galactosidase activity) is very restricted but overlaps better with that of presenilins and Kv4 channels than with dynorphin, suggesting that calsenilin may regulate presenilin and Kv4 channels in brain. Aβ peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent γ-cleavage in vivo. Furthermore, long-term potentiation (LTP) in dentate gyrus of hippocampus, in which calsenilin is strongly and selectively expressed, is enhanced in calsenilin knock-out mice. This enhancement of LTP coincides with a downregulation of the Kv4 channel-dependent A-type current and can be mimicked in wild-type animals by a Kv4 channel blocker. The data presented here show that lack of calsenilin affects both Aβ formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport.

Original languageEnglish (US)
Pages (from-to)9097-9106
Number of pages10
JournalJournal of Neuroscience
Volume23
Issue number27
DOIs
StatePublished - Oct 8 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience

Keywords

  • A-type current
  • APP
  • Apoptosis
  • Calcium
  • DREAM
  • KChIP
  • Kv4 channel
  • Long-term potentiation
  • Neuronal calcium sensor
  • Presenilin

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