The SK2-long isoform directs synaptic localization and function of SK2-containing channels

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Abstract

SK2-containing channels are expressed in the postsynaptic density (PSD) of dendritic spines on mouse hippocampal area CA1 pyramidal neurons and influence synaptic responses, plasticity and learning. The Sk2 gene (also known as Kcnn2) encodes two isoforms that differ only in the length of their N-terminal domains. SK2-long (SK2-L) and SK2-short (SK2-S) are coexpressed in CA1 pyramidal neurons and likely form heteromeric channels. In mice lacking SK2-L (SK2-S only mice), SK2-S–containing channels were expressed in the extrasynaptic membrane, but were excluded from the PSD. The SK channel contribution to excitatory postsynaptic potentials was absent in SK2-S only mice and was restored by SK2-L re-expression. Blocking SK channels increased the amount of long-term potentiation induced in area CA1 in slices from wild-type mice but had no effect in slices from SK2-S only mice. Furthermore, SK2-S only mice outperformed wild-type mice in the novel object recognition task. These results indicate that SK2-L directs synaptic SK2-containing channel expression and is important for normal synaptic signaling, plasticity and learning.

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Figure 1: Subcellular localization of SK2-L in dendritic spines of wild-type CA1 pyramidal neurons.
Figure 2: Sk2 gene locus and western blot.
Figure 3: Subcellular localization of SK2 in wild-type and SK2-S only CA1 pyramidal neurons.
Figure 4: SK2-containing channels are expressed in the plasma membrane of SK2-S only CA1 pyramidal neurons.
Figure 5: SK2-L re-expression re-instates apamin sensitivity to synaptically evoked glutamatergic EPSPs.
Figure 6: SK channel activity affects LTP in wild-type, but not SK2-S only, mice.
Figure 7: Spatial memory is impaired in SK2-S only mice.

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Acknowledgements

We thank K. Vick, C. Christakis and K. Smith (all from FAU) for their expert assistance with the behavioral testing. This work was supported by US National Institutes of Health grants NS038880 (J.P.A.), MH081860-01 (J.M.), F32MH080480 (M.T.L.) and MH0876591-01 (R.W.S.), National Science Foundation grant IBN 0630522 (R.W.S.), and grants from the Spanish Ministry of Education and Science (CONSOLIDER CSD2008-00005) and Consejería de Educación y Ciencia, Junta de Comunidades de Castilla-La Mancha (PPII11-0284-9301) and Spanish Ministry of Education and Science (BFU-2009-08404/BFI) to R.L.

Author information

D.A., M.T.L., K.W. and N.K. performed the electrophysiology. C.T.B. performed molecular biology and biochemistry. R.L., C.B.-M. and R.S. were responsible for iEM. M.W. provided the antibodies. R.W.S. was responsible for the behavioral testing. J.P.A. and J.M. wrote the manuscript.

Correspondence to James Maylie or John P Adelman.

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