Altered Abeta formation and long-term potentiation in a calsenilin knock-out.
Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a beta-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 beta-galactosidase gene. We found that calsenilin expression (as represented by beta-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. Abeta peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent gamma-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 Abeta formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport.
Lilliehook
Christina
C
Laboratory of Molecular Neuropsychiatry and Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA.
Bozdagi
Ozlem
O
Yao
Jun
J
Gomez-Ramirez
Manuel
M
Zaidi
Nikhat F
NF
Wasco
Wilma
W
Gandy
Sam
S
Santucci
Anthony C
AC
Haroutunian
Vahram
V
Huntley
George W
GW
Buxbaum
Joseph D
JD
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D002451:Cell Compartmentation / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D051605:Kv Channel-Interacting Proteins; D017774:Long-Term Potentiation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D051672:Shal Potassium Channels; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; C496756:Csen protein, mouse; D051605:Kv Channel-Interacting Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012097:Repressor Proteins; D051672:Shal Potassium Channels; D001616:beta-Galactosidase