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The Journal of Neuroscience, October 8, 2003, 23(27):9097-9106

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Cellular/Molecular
Altered A Formation and Long-Term Potentiation in a Calsenilin Knock-Out

Christina Lilliehook,^1,2,3 Ozlem Bozdagi,³ Jun Yao,⁴ Manuel Gomez-Ramirez,⁵ Nikhat F. Zaidi,⁶ Wilma Wasco,⁶ Sam Gandy,⁴ Anthony C. Santucci,^2,5 Vahram Haroutunian,^2,3,7 George W. Huntley,³ and Joseph D. Buxbaum^1,2,3

¹Laboratory of Molecular Neuropsychiatry and Departments of ²Psychiatry and ³Neurobiology, Mount Sinai School of Medicine of New York University, New York, New York 10029, ⁴Farber Institute for Neurosciences of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, ⁵Department of Psychology, Manhattanville College, Purchase, New York 10577, ⁶Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, and ⁷Department of Psychiatry, Medical Research Building, Bronx Veterans Medical Center, Bronx, New York 10468

Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a -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 -galactosidase gene. We found that calsenilin expression (as represented by -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. A peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent -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 A formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport.

Key words: KChIP; DREAM; presenilin; APP; A; apoptosis; calcium; neuronal calcium sensor; Kv4 channel; long-term potentiation; A-type current

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Received April 7, 2003; revised August 14, 2003; accepted August 14, 2003.

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