Increasing SK2 channel activity impairs associative learning

McKay, Bridget M.; Oh, M. Matthew; Galvez, Roberto; Burgdorf, Jeffrey; Kroes, Roger A.; Weiss, Craig; Adelman, John P.; Moskal, Joseph R.; Disterhoft, John F.

doi:10.1152/jn.00025.2012

Cited by 43 publications

(46 citation statements)

References 51 publications

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“…We previously showed that a semi-chronic treatment with CX929 reversed the behavioral deficit and re-established normal levels of freezing in response to context and cue (Baudry et al, 2012). Manipulations of SK2 activity have been shown to influence learning performance in various paradigms (Deschaux et al, 1997; McKay et al, 2012; Stackman et al, 2002). A recent study showed that apamin enhanced contextual fear memory in WT mice conditioned with one CS-US pairing protocol, but not with three CS-US pairings (Vick et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

et al. 2015

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Summary Gated solely by activity-induced changes in intracellular calcium, small conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and over-expression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

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Section: Discussionmentioning

confidence: 99%

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

et al. 2015

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“…The AHP is larger in aged compared to young animals (Landfield & Pitler, 1984; Potier et al , 1992; Disterhoft et al , 1996; Hemond & Jaffe, 2005; Tombaugh et al , 2005; Kumar & Foster, 2007; Gant et al , 2011), thus reducing the amplitude or duration of this hyperpolarizing potential may help combat age-related memory dysregulation by allowing cells to participate within a functional network (Gant & Thibault, 2009). Indeed, it has been shown that elevating potassium channel activity impairs learning (McKay et al , 2012), while lowering L-VGCC contribution to the AHP reduces the AHP (Moyer et al , 1992; Gamelli et al , 2011) and enhances learning (Deyo et al , 1989; Moyer et al , 1992). Moreover, increasing cholinergic neurotransmission which enhances cellular excitability also can enhance learning (Saar et al , 1998; Oh et al , 1999; Saar et al , 2001; Disterhoft & Oh, 2006).…”

Section: Discussionmentioning

confidence: 99%

Novel calcium-related targets of insulin in hippocampal neurons

et al. 2017

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Both insulin signaling disruption and Ca2+ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca2+-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca2+-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in the brain. Indeed, increasing insulin signaling in the brain via intranasal delivery has yielded promising results such as improving memory in both clinical and animal studies. However, while several mechanisms have been proposed, few have focused on regulation on intracellular Ca2+. In the present study, we further examined the effects of acute insulin on calcium pathways in primary hippocampal neurons in culture. Using the whole-cell patch-clamp technique, we found that acute insulin delivery reduced voltage-gated calcium currents. Fura-2 imaging was used to also address acute insulin effects on spontaneous and depolarization-mediated Ca2+ transients. Results indicate that insulin reduced Ca2+ transients, which appears to have involved a reduction in ryanodine receptor function. Together, these results suggest insulin regulates pathways that control intracellular Ca2+ which may reduce the AHP and improve memory. This may be one mechanism contributing to improved memory recall in response to intranasal insulin therapy in the clinic.

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“…Activation of SK channels blocks conditioning-induced excitability changes in both CA1 pyramidal neurons and interneurons, and impairs learning (McKay et al, 2012, 2013). Because SK channels play a critical role in regulating after hyperpolarizing (AHP) currents and thus firing rates in CA1 (Pedarzani et al, 2005), excitability changes associated with SK channel reductions may mediate the firing rate increases we see in vivo after CFC.…”

Section: Discussionmentioning

confidence: 99%

CA1 hippocampal network activity changes during sleep-dependent memory consolidation

Ognjanovski

Maruyama

Lashner

et al. 2014

Front. Syst. Neurosci.

117

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A period of sleep over the first few hours following single-trial contextual fear conditioning (CFC) is essential for hippocampally-mediated memory consolidation. Recent studies have uncovered intracellular mechanisms required for memory formation which are affected by post-conditioning sleep and sleep deprivation. However, almost nothing is known about the circuit-level activity changes during sleep that underlie activation of these intracellular pathways. Here we continuously recorded from the CA1 region of freely-behaving mice to characterize neuronal and network activity changes occurring during active memory consolidation. C57BL/6J mice were implanted with custom stereotrode recording arrays to monitor activity of individual CA1 neurons, local field potentials (LFPs), and electromyographic activity. Sleep architecture and state-specific CA1 activity patterns were assessed during a 24 h baseline recording period, and for 24 h following either single-trial CFC or Sham conditioning. We find that consolidation of CFC is not associated with significant sleep architecture changes, but is accompanied by long-lasting increases in CA1 neuronal firing, as well as increases in delta, theta, and gamma-frequency CA1 LFP activity. These changes occurred in both sleep and wakefulness, and may drive synaptic plasticity within the hippocampus during memory formation. We also find that functional connectivity within the CA1 network, assessed through functional clustering algorithm (FCA) analysis of spike timing relationships among recorded neurons, becomes more stable during consolidation of CFC. This increase in network stability was not present following Sham conditioning, was most evident during post-CFC slow wave sleep (SWS), and was negligible during post-CFC wakefulness. Thus in the interval between encoding and recall, SWS may stabilize the hippocampal contextual fear memory (CFM) trace by promoting CA1 network stability.

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Increasing SK2 channel activity impairs associative learning

Abstract: McKay BM, Oh MM, Galvez R, Burgdorf J, Kroes RA, Weiss C, Adelman JP, Moskal JR, Disterhoft JF. Increasing SK2 channel activity impairs associative learning.

Cited by 43 publications

References 51 publications

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

Novel calcium-related targets of insulin in hippocampal neurons

CA1 hippocampal network activity changes during sleep-dependent memory consolidation

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