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The Journal of Neuroscience, February 8, 2006, 26(6):1844-1853; doi:10.1523/JNEUROSCI.4106-05.2006

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Behavioral/Systems/Cognitive
Small-Conductance Ca²⁺-Activated K⁺ Channel Type 2 (SK2) Modulates Hippocampal Learning, Memory, and Synaptic Plasticity

Rebecca S. Hammond,¹ Chris T. Bond,³ Timothy Strassmaier,³ Thu Jennifer Ngo-Anh,³ John P. Adelman,³ James Maylie,² and Robert W. Stackman¹

¹Departments of Behavioral Neuroscience and ²Obstetrics and Gynecology and ³Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239-3089

Correspondence should be addressed to Dr. Robert W. Stackman at his present address: Department of Psychology, BS 101, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991. Email: rstackma{at}fau.edu

Apamin-sensitive, small-conductance, Ca²⁺-activated K⁺ channels (SK channels) modulate neuronal excitability in CA1 neurons. Blocking all SK channel subtypes with apamin facilitates the induction of hippocampal synaptic plasticity and enhances hippocampal learning. In CA1 dendrites, SK channels are activated by Ca²⁺ through NMDA receptors and restrict glutamate-mediated EPSPs. Studies of SK channel knock-out mice reveal that of the three apamin-sensitive SK channel subunits (SK1–SK3), only SK2 subunits are necessary for the apamin-sensitive currents in CA1 hippocampal neurons. To determine the specific influence of SK2 channels on hippocampal synaptic plasticity, learning, and memory, we used gene targeting through homologous recombination in embryonic stem cells to generate transgenic mice that overexpress SK2 subunits by 10-fold (SK2+/T). In these mice, the apamin-sensitive current in CA1 neurons was increased by approximately fourfold, relative to wild-type (WT) littermates. In addition, the amplitude of synaptically evoked EPSPs recorded from SK2+/T CA1 neurons increased twice as much in response to SK channel blockade relative to EPSPs recorded from WT CA1 neurons. Consistent with this, SK2 overexpression reduced long-term potentiation after high-frequency stimulation compared with WT littermates and severely impaired learning in both hippocampus- and amygdala-dependent tasks. We conclude that SK2 channels regulate hippocampal synaptic plasticity and play a critical role in modulating mechanisms of learning and memory.

Key words: hippocampus; potassium channel; long-term potentiation; spatial learning; spatial memory; fear conditioning

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Received Sept. 27, 2005; revised Dec. 18, 2005; accepted Dec. 21, 2005.

Correspondence should be addressed to Dr. Robert W. Stackman at his present address: Department of Psychology, BS 101, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991. Email: rstackma{at}fau.edu

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