βCaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses

Woerden, Geeske M. van; Hoebeek, Freek E.; Gao, Zhenyu; Nagaraja, Raghavendra Y.; Hoogenraad, Casper C.; Kushner, Steven A.; Hansel, Christian; Zeeuw, Chris I. De; Elgersma, Ype

doi:10.1038/nn.2329

Cited by 124 publications

(173 citation statements)

References 15 publications

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“…We found no significant change in the density of spines (wild-type mice: 6.35 Ϯ 0.36 n ϭ 15 cells from 3 mice; Camk2b Ϫ/Ϫ mice: 7.07 Ϯ 0.61 n ϭ 15 from 3 mice; unpaired two-tailed t test, t (28) ϭ 1.8, p ϭ 0.09) (Fig. 1d), which is consistent with our previous findings for the cerebellum (van Woerden et al, 2009). Together, these data show that gross neuronal development is preserved in Camk2b Ϫ/Ϫ mice.…”

Section: Camk2bsupporting

confidence: 92%

“…Inducible overexpression of ␤CaMKII in the dentate gyrus did not affect acquisition of hippocampal learning, but did affect the long-term consolidation of memories (Cho et al, 2007). Additionally, it was shown that the absence of ␤CaMKII reverses the polarity of plasticity at cerebellar parallel fiber-Purkinje cell synapses and causes significant cerebellar learning deficits (van Woerden et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

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CaMKII Plays a Nonenzymatic Role in Hippocampal Synaptic Plasticity and Learning by Targeting CaMKII to Synapses

Borgesius¹,

Woerden²,

Buitendijk³

et al. 2011

Journal of Neuroscience

110

122

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The calcium/calmodulin-dependent kinase type II (CaMKII) holoenzyme of the forebrain predominantly consists of heteromeric complexes of the ␣CaMKII and ␤CaMKII isoforms. Yet, in contrast to ␣CaMKII, the role of ␤CaMKII in hippocampal synaptic plasticity and learning has not been investigated. Here, we compare two targeted Camk2b mouse mutants to study the role of ␤CaMKII in hippocampal function. Using a Camk2b Ϫ/Ϫ mutant, in which ␤CaMKII is absent, we show that both hippocampal-dependent learning and Schaffer collateral-CA1 long-term potentiation (LTP) are highly dependent upon the presence of ␤CaMKII. We further show that ␤CaMKII is required for proper targeting of ␣CaMKII to the synapse, indicating that ␤CaMKII regulates the distribution of ␣CaMKII between the synaptic pool and the adjacent dendritic shaft. In contrast, localization of ␣CaMKII, hippocampal synaptic plasticity and learning were unaffected in the Camk2b A303R mutant, in which the calcium/calmodulin-dependent activation of ␤CaMKII is prevented, while the F-actin binding and bundling property is preserved. This indicates that the calcium/calmodulin-dependent kinase activity of ␤CaMKII is fully dispensable for hippocampal learning, LTP, and targeting of ␣CaMKII, but implies a critical role for the F-actin binding and bundling properties of ␤CaMKII in synaptic function. Together, our data provide compelling support for a model of CaMKII function in which ␣CaMKII and ␤CaMKII act in concert, but with distinct functions, to regulate hippocampal synaptic plasticity and learning.

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Section: Camk2bsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

CaMKII Plays a Nonenzymatic Role in Hippocampal Synaptic Plasticity and Learning by Targeting CaMKII to Synapses

Borgesius¹,

Woerden²,

Buitendijk³

et al. 2011

Journal of Neuroscience

110

122

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“…It is believed that memory is supported by the balance between the formation and recovery processes (42). Previous studies have shown that kinases (43,44) and phosphatases (33) act as switches of synaptic plasticity, thus regulating memory formation and reversal processes (45,46). Thus, the slow formation of memory by massed training may allow strong reversal processes and induce the rapid decay of long-lasting memory, whereas the rapid formation of memory observed in spaced training may strongly suppress reversal processes.…”

Section: Discussionmentioning

confidence: 99%

Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning

Aziz

Wang

Kesaf

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Long-lasting memories are formed when the stimulus is temporally distributed (spacing effect). However, the synaptic mechanisms underlying this robust phenomenon and the precise time course of the synaptic modifications that occur during learning remain unclear. Here we examined the adaptation of horizontal optokinetic response in mice that underwent 1 h of massed and spaced training at varying intervals. Despite similar acquisition by all training protocols, 1 h of spacing produced the highest memory retention at 24 h, which lasted for 1 mo. The distinct kinetics of memory are strongly correlated with the reduction of floccular parallel fiber-Purkinje cell synapses but not with AMPA receptor (AMPAR) number and synapse size. After the spaced training, we observed 25%, 23%, and 12% reduction in AMPAR density, synapse size, and synapse number, respectively. Four hours after the spaced training, half of the synapses and Purkinje cell spines had been eliminated, whereas AMPAR density and synapse size were recovered in remaining synapses. Surprisingly, massed training also produced long-term memory and halving of synapses; however, this occurred slowly over days, and the memory lasted for only 1 wk. This distinct kinetics of structural plasticity may serve as a basis for unique temporal profiles in the formation and decay of memory with or without intervals. cerebellar motor learning | AMPA receptor reduction | synapse shrinkage and elimination D uring learning, memories are formed in a specific population of neuronal circuits and are consolidated for persistence (1, 2). These memory processes are supported by discrete subcellular events such as reversible modifications in the efficacy of synaptic transmission (3-5) or persistent structural modifications in the size and number of synaptic connections (6-8). However, how these synaptic modifications relate to the dynamics of formation and decay of memories in behaving animals remains elusive. Memory formation and its persistence are also sensitive to the temporal features of stimulus presentation, as observed in the well-known "spacing effect." Training trials that include resting intervals between them (spaced training) produce stronger and longer-lasting memories than do the same number of trials with no intervals (massed training) (9). The spacing effect has been observed in a variety of explicit and implicit memory tasks (10-13), and the molecular mechanisms supporting this phenomenon have been reported (14-18). Various intracellular signaling molecules such as CREB (19), mitogen-activated protein (MAP) kinase (20, 21), and PKA (22, 23) underlie the spacing effect and are implicated in the remodeling of neuronal structures (23). In vitro studies showed that spaced stimuli induced the protrusion of new filopodia (20) and the recruitment of new synapses (24) in hippocampal neurons. However, despite the existence of numerous behavioral and molecular studies, no conjoint study has elucidated the synaptic correlates that underpin the expression of the spacing effect du...

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“…β-CaMKII is expressed in Purkinje cells as well (28), but the inhibitory autophosphorylation has only been examined in α-CaMKII and has been shown to have a dominant negative effect on the holoenzyme (27). Both α-CaMKII and β-CaMKII are essential for proper LTD induction (28,29). CaMKII promotes LTD by suppressing the activity of protein phosphatase 2A through negative regulation of phosphodiesterase 1 and subsequent disinhibition of a cGMP/protein kinase G pathway (30).…”

Section: Significancementioning

confidence: 99%

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Piochon

Titley

Simmons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes. We addressed this problem at cerebellar parallel fiber-Purkinje cell synapses, which can undergo LTD or LTP in response to 1-Hz and 100-Hz stimulation. We observed that high-frequency activation elicits larger spine calcium transients than low-frequency stimulation under all stimulus conditions, but, regardless of activation frequency, climbing fiber (CF) coactivation provides an instructive signal that further enhances calcium transients and promotes LTD. At both frequencies, buffering calcium prevents LTD induction and LTP results instead, identifying the enhanced calcium signal amplitude as the critical parameter contributed by the instructive CF signal. These observations show that it is not absolute calcium amplitudes that determine whether LTD or LTP is evoked but, instead, the LTD threshold slides, thus preserving the requirement for relatively larger calcium transients for LTD than for LTP induction at any given stimulus frequency. Cerebellar LTD depends on the activation of calcium/ calmodulin-dependent kinase II (CaMKII). Using genetically modified (TT305/6VA and T305D) mice, we identified α-CaMKII inhibition upon autophosphorylation at Thr305/306 as a molecular event underlying the threshold shift. This mechanism enables frequencyindependent plasticity control by the instructive CF signal based on relative, not absolute, calcium thresholds.S ynaptic activation frequency is an important factor in the induction of long-term potentiation (LTP) and long-term depression (LTD). For example, it has been shown at Schaffer collateral-CA1 pyramidal cell synapses that application of 900 pulses at 1-3 Hz causes LTD, whereas the same number of pulses applied at 50 Hz causes LTP (1). However, LTP and LTD can also be induced at the same stimulus frequency. This phenomenon has been demonstrated at hippocampal, neocortical, and cerebellar synapses, where potentiation and depression mechanisms operate over a wide range of activation frequencies (2-7). In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, ...

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βCaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses

Cited by 124 publications

References 15 publications

CaMKII Plays a Nonenzymatic Role in Hippocampal Synaptic Plasticity and Learning by Targeting CaMKII to Synapses

CaMKII Plays a Nonenzymatic Role in Hippocampal Synaptic Plasticity and Learning by Targeting CaMKII to Synapses

Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

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