Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory.
Small-conductance, Ca2+ activated K+ channels (SK channels) are expressed at high levels in brain regions responsible for learning and memory. In the current study we characterized the contribution of SK2 channels to synaptic plasticity and to different phases of hippocampal memory formation. Selective SK2 antisense-treatment facilitated basal synaptic transmission and theta-burst induced LTP in hippocampal brain slices. Using the selective SK2 antagonist Lei-Dab7 or SK2 antisense probes, we found that hippocampal SK2 channels are critical during two different time windows: 1) blockade of SK2 channels before the training impaired fear memory, whereas, 2) blockade of SK2 channels immediately after the training enhanced contextual fear memory. We provided the evidence that the post-training cleavage of the SK2 channels was responsible for the observed bidirectional effect of SK2 channel blockade on memory consolidation. Thus, Lei-Dab7-injection before training impaired the C-terminal cleavage of SK2 channels, while Lei-Dab7 given immediately after training facilitated the C-terminal cleavage. Application of the synthetic peptide comprising a leucine-zipper domain of the C-terminal fragment to Jurkat cells impaired SK2 channel-mediated currents, indicating that the endogenously cleaved fragment might exert its effects on memory formation by blocking SK2 channel-mediated currents. Our present findings suggest that SK2 channel proteins contribute to synaptic plasticity and memory not only as ion channels but also by additionally generating a SK2 C-terminal fragment, involved in both processes. The modulation of fear memory by down-regulating SK2 C-terminal cleavage might have applicability in the treatment of anxiety disorders in which fear conditioning is enhanced.
Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, United States of America.
Saravana R K
SR
Murthy
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
Tessi
T
Sherrin
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Laboratory of Cell and Molecular Signaling, The Queen's Medical Center, Honolulu, Hawaii, United States of America.
Chad
C
Jansen
Isala Academy, Isala Clinic, Zwolle, The Netherlands.
Ingrid
I
Nijholt
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
Michael
M
Robles
Department of Pharmacology and Toxicology, Philipps-University Marburg, Marburg, Germany.
Amalia M
AM
Dolga
Laboratoire INSERM UMR1097, Parc scientifique et technologique de Luminy, Marseille, cedex 09, France.
Nicolas
N
Andreotti
Laboratoire INSERM UMR1097, Parc scientifique et technologique de Luminy, Marseille, cedex 09, France.
Jean-Marc
JM
Sabatier
Division for Molecular and Cellular Pharmacology, Medical University Innsbruck, Innsbruck, Austria.
Hans-Guenther
HG
Knaus
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Laboratory of Cell and Molecular Signaling, The Queen's Medical Center, Honolulu, Hawaii, United States of America.
Reinhold
R
Penner
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
Cedomir
C
Todorovic
Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America; Institute for Neuropathology, University of Freiburg, Freiburg, Germany.
Thomas
T
Blank
D000818:Animals; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
D051640:Small-Conductance Calcium-Activated Potassium Channels