Inhibitory Autophosphorylation of CaMKII Controls PSD Association, Plasticity, and Learning

Elgersma, Ype; Fedorov, N. A.; Ikonen, Sami; Choi, Esther; Elgersma, Minetta; Carvalho, Ofélia P.; Giese, K. Peter; Silva, Alcino J.

doi:10.1016/s0896-6273(02)01007-3

Cited by 275 publications

(351 citation statements)

References 44 publications

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“…This description profile matches the inhibitory autophosphorylation that has been described for the alpha subunit of calcium/calmodulin-dependent kinase II (α-CaMKII) at Thr305 and Thr306, which lowers the affinity of CaMKII for CaM, and thus reduces Ca/CaM-mediated activation (27). 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).…”

Section: Significancesupporting

confidence: 78%

“…Negative regulation of CaMKII by Thr305/ 306 autophosphorylation requires prior calcium/calmodulin-mediated activation of CaMKII and subsequent calmodulin dissociation (31). Moreover, it has been shown that Thr305/306 phosphorylation, triggered by 10-Hz priming, reduces hippocampal LTP (32), whereas genetic manipulation of the Thr305/306 phosphorylation site lowers the LTP threshold and prevents priming (27,32). Thus, CaMKII inhibitory autophosphorylation depends on previous calcium signaling and directly affects the kinase/phosphatase balance, thus fulfilling the two requirements outlined above.…”

Section: Significancementioning

confidence: 99%

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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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Section: Significancesupporting

confidence: 78%

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.

Self Cite

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“…To test whether binding depended on the phosphorylation state of ␣CaMKII, we generated a double mutant (TT305/6VA) where two inhibitory autophosphorylation sites were removed. The threshold for kinase activation and for LTP induction is known to be lowered in the TT305/6VA mutant (21)(22)(23). Indeed, cells transfected with mutant ␣CaMKII had a significantly higher unrecoverable fraction of 42% Ϯ 28% (P Ͻ 0.05).…”

Section: Spine Volume Changes Induced By Pairing Of Glutamate Uncaginmentioning

confidence: 99%

Optical induction of plasticity at single synapses reveals input-specific accumulation of αCaMKII

Zhang

Holbro²,

Oertner³

2008

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

125

113

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Long-term potentiation (LTP), a form of synaptic plasticity, is a primary experimental model for understanding learning and memory formation. Here, we use light-activated channelrhodopsin-2 (ChR2) as a tool to study the molecular events that occur in dendritic spines of CA1 pyramidal cells during LTP induction. Two-photon uncaging of MNI-glutamate allowed us to selectively activate excitatory synapses on optically identified spines while ChR2 provided independent control of postsynaptic depolarization by blue light. Pairing of these optical stimuli induced lasting increase of spine volume and triggered translocation of ␣CaMKII to the stimulated spines. No changes in ␣CaMKII concentration or cytoplasmic volume were observed in neighboring spines on the same dendrite, providing evidence that ␣CaMKII accumulation at postsynaptic sites is a synapse-specific memory trace of coincident activity.channelrhodopsin-2 ͉ dendritic spines ͉ synaptic plasticity ͉ two-photon uncaging ͉ MNI-glutamate A ctivity-dependent changes in synaptic strength are generally considered to be the cellular basis of learning and memory (1). Long-term potentiation (LTP), the most extensively studied form of such synaptic plasticity, can be triggered within seconds by coincident activity in presynaptic and postsynaptic cells. The possible structural modifications that occur at synapses where LTP has been induced are poorly known because of the difficulty of simultaneously measuring functional and morphological parameters at individual synapses. Furthermore, it is controversial whether neighboring synapses can be modified independently (2-4). In a recent report, it has been shown that spatially clustered synapses can cooperate in the induction of plasticity and that cytoplasmic factors are responsible for this functional cross-talk (5). The identity of these diffusible factors, however, has not been clarified.A key player in the LTP signaling cascade is ␣CaMKII, which is thought to function as a molecular switch: Following activation by Ca 2ϩ -calmodulin, it can stay active for prolonged periods of time via autophosphorylation (6, 7). Reports that brief application of glutamate or NMDA to cultured hippocampal neurons induces CaMKII accumulation in spines (8-10) have created much interest because ␣CaMKII activation is both necessary and sufficient to induce synaptic plasticity (6, 11). It has been suggested that postsynaptic accumulation of ␣CaMKII could be responsible for the synapse-specificity of LTP, because it localizes the putative activated kinase close to its substrates, e.g., AMPA receptors (7, 12) and protects it from dephosphorylation (13). However, a crucial prediction of this hypothesis, namely that ␣CaMKII accumulates specifically and exclusively at synapses that undergo LTP, has never been tested experimentally.To address whether ␣CaMKII accumulates specifically in spines experiencing coincident activity, we developed an alloptical pairing protocol to induce synaptic plasticity at identified spines, combining two-photon uncaging of ...

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“…Phosphorylation of these residues inhibits kinase binding to isolated PSDs (Strack et al, 1997b), α-actinin (Robison et al, 2005), and the NMDAR subunits NR1 and NR2B (Leonard et al, 2002). In addition, T305/6 phosphorylation increases the dissociation rate of CaMKII from the PSD (Shen et al, 2000), and mimicking phosphorylation on these residues prevents while inhibiting phosphorylation enhances PSD association of the kinase (Elgersma et al, 2002). Furthermore, CaMKII interaction with NR2B, which is enriched at the PSD, has been shown to suppress T305/6 phosphorylation (Bayer et al, 2001), and T306 phosphorylation leads to CaMKII dissociation from the synapse associated protein Camguk in Drosophila (Lu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

αCaMKII autophosphorylation levels differ depending on subcellular localization

et al. 2007

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Calcium/calmodulin-dependent protein kinase II (CaMKII) has important roles in many processes in the central nervous system. It is enriched at the post-synaptic density (PSD), a localization which is thought to be critical for many of its proposed neuronal functions. In order to better understand the mechanisms that regulate association of CaMKII with the PSD, we compared the levels of autophosphorylation between PSD-associated kinase and kinase in other parts of the neuron. We were surprised to find that αCaMKII in a PSD-enriched fraction prepared from recovered hippocampal CA1-minislices had a relatively low level of threonine 286 (T286) phosphorylation and a relatively high level of threonine 305 (T305) phosphorylation. Furthermore, when the minislices were subjected to a treatment that mimics ischemic conditions, there was a significant translocation of αCaMKII to the PSD-enriched fraction accompanied with a dramatic reduction in T286 phosphorylation levels throughout the neuron. These findings have important implications for our understanding of the role of autophosphorylation in the localization of CaMKII.

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Inhibitory Autophosphorylation of CaMKII Controls PSD Association, Plasticity, and Learning

Cited by 275 publications

References 44 publications

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

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

Optical induction of plasticity at single synapses reveals input-specific accumulation of αCaMKII

αCaMKII autophosphorylation levels differ depending on subcellular localization

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