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

Abstract

Apamin-sensitive, small-conductance, Ca 2ϩ -activated K ϩ 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 Ca 2ϩ 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 (SK2ϩ/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 SK2ϩ/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.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…For example, the decrease in SK channel function following CIE treatment observed in many regions including the OFC would be expected to enhance synaptic efficacy and plasticity. In support of this, results from previous studies show that blocking these channels facilitates LTP and enhances learning and memory (Blank et al, 2003;Brennan et al, 2008;Hammond et al, 2006;Stackman et al, 2002), whereas overexpression of SK channels reduces LTP and impairs hippocampus-, amygdala-, and mPFC-dependent learning tasks. In addition to changes in glutamate receptor expression and function described above, alterations in dendritic Figure 8 Chronic intermittent ethanol (CIE) exposure suppresses the ability of the GlyT1 transport inhibitor sarcosine to reduce spiking in lateral orbitofrontal cortex (lOFC) neurons.…”

Inhibition of the Ca2+-Dependent K+Channel,KCNN4/KCa3.1, Improves Tissue Protection and Locomotor Recovery after Spinal Cord Injury

“…From in vitro studies, we identified several roles for KCa3.1 in microglial activation (Khanna et al, 2001;Kaushal et al, 2007), but its roles in astrocytes, neurons, and oligodendrocytes have not been addressed. Other SK channels (KCa2.2, KCa2.3) have been implicated in the slow afterhyperpolarization that regulates neuron firing frequency (Hammond et al, 2006;Faber, 2009).…”

CyPPA, a positive modulator of small-conductance Ca2+-activated K+ channels, inhibits phasic uterine contractions and delays preterm birth in mice

“…The current study did not clearly delineate relative contributions of K Ca 2.2 and 2.3 although K Ca 2.3 channels were found to be highly localized in the cell periphery, indicative of their function as plasma membrane ion channels. Although overexpression and suppression of K Ca 2.2 levels in genetically altered mice have been linked to pup viability (5,13,20), specific effects on gestation and parturition have not been reported. In fact, following suppression of K Ca 2.3 expression, the global K Ca 2 blocker apamin does not significantly alter uterine contractions (7), questioning any functional impact of other isoforms.…”