Small-conductance Ca2+-activated potassium type 2 channels regulate the formation of contextual fear memory

Saravana R K Murthy, Tessi Sherrin, Chad Jansen, Ingrid Nijholt, Michael Robles, Amalia M Dolga, Nicolas Andreotti, Jean-Marc Sabatier, Hans-Guenther Knaus, Reinhold Penner, Cedomir Todorovic, Thomas Blank

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10 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article numbere0127264
Number of pages17
JournalPLoS ONE
Volume10
Issue number5
DOIs
Publication statusPublished - 4-May-2015
Externally publishedYes

Keywords

  • RECEPTORS
  • EXPRESSION
  • LONG-TERM POTENTIATION
  • K+ CHANNELS
  • SYNAPTIC PLASTICITY
  • CONJUNCTIVE REPRESENTATIONS
  • SK2 CHANNELS
  • C-TERMINUS
  • HIPPOCAMPUS
  • BRAIN

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