Article

Kinase activity is not required for alpha CaMKII-dependent presynaptic plasticity at CA3-CA1 synapses

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Nature Neuroscience (Impact Factor: 14.98). 10/2007; 10(9):1125-7. DOI: 10.1038/nn1946
Source: PubMed

ABSTRACT Using targeted mouse mutants and pharmacologic inhibition of alphaCaMKII, we demonstrate that the alphaCaMKII protein, but not its activation, autophosphorylation or its ability to phosphorylate synapsin I, is required for normal short-term presynaptic plasticity. Furthermore, alphaCaMKII regulates the number of docked vesicles independent of its ability to be activated. These results indicate that alphaCaMKII has a nonenzymatic role in short-term presynaptic plasticity at hippocampal CA3-CA1 synapses.

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Available from: Karl Peter Giese, Aug 28, 2015
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    • "The generation of null mutant mice that do not express aCaMKII protein allowed to demonstrate that aCaMKII controlled presynaptic plasticity (Hinds et al. 2003) in a way independent of its kinase activity (Hojjati et al. 2007). Postsynaptic LTP was also impaired in these mice (Silva et al. 1992b) but not totally absent (Hinds et al. 1998) suggesting a compensatory role of bCaMKII which can be autophosphorylated at T287 (Brocke et al. 1999). "
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    ABSTRACT: α-calcium/calmodulin-dependent protein kinase (αCaMKII) T286-autophosphorylation provides a short-term molecular memory that was thought to be required for LTP and for learning and memory. However, it has been shown that learning can occur in αCaMKII-T286A mutant mice after a massed training protocol. This raises the question of whether there might be a form of LTP in these mice that can occur without T286 autophosphorylation. In this study, we confirmed that in CA1 pyramidal cells, LTP induced in acute hippocampal slices, after a recovery period in an interface chamber, is strictly dependent on postsynaptic αCaMKII autophosphorylation. However, we demonstrated that αCaMKII-autophosphorylation-independent plasticity can occur in the hippocampus but at the expense of synaptic specificity. This nonspecific LTP was observed in mutant and wild-type mice after a recovery period in a submersion chamber and was independent of NMDA receptors. Moreover, when slices prepared from mutant mice were preincubated during 2 h with rapamycin, high-frequency trains induced a synapse-specific LTP which was added to the nonspecific LTP. This specific LTP was related to an increase in the duration and the amplitude of NMDA receptor-mediated response induced by rapamycin.
    Learning & memory (Cold Spring Harbor, N.Y.) 11/2014; 21(11):616-26. DOI:10.1101/lm.035972.114 · 4.38 Impact Factor
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    • "CaMKII is highly expressed in dopamine terminals, which densely innervate the striatum, where it stimulates dopamine efflux via the dopamine transporter in the presence of amphetamine [51]. In addition, CaMKII is present in glutamatergic projections, which form the presynaptic terminal onto MSN spines and dendrites [33], [51], where it may modulate release events [39], [43], [44], [45]. Our transgenic strategy resulted in the selective expression of the CaMKII inhibitor in the postsynaptic MSN, where it cannot directly affect the function of the glutamatergic and dopaminergic terminals, consistent with the lack of change in glutamate release parameters in EAC3I MSNs (Figures 3, 4). "
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    ABSTRACT: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I-expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response.
    PLoS ONE 09/2012; 7(9):e45323. DOI:10.1371/journal.pone.0045323 · 3.23 Impact Factor
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    • "This is because αCaMKII has various functions and only a subset of these functions is impaired in the αCaMKIIT286A mutants. For example, αCaMKII has a structural function that is independent from the T286 autophosphorylation [28]. Thus, it is not surprising that heterozygous αCaMKII null mutants, but not αCaMKIIT286A mutants, have impaired remote contextual LTM. "
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    ABSTRACT: The alpha-isoform of calcium/calmodulin-dependent kinase II (αCaMKII) is a major synaptic kinase that undergoes autophosphorylation after NMDA receptor activation, switching the kinase into a calcium-independent activity state. This αCaMKII autophosphorylation is essential for NMDA receptor-dependent long-term potentiation (LTP), induced by a single tetanus, in hippocampal area CA1 and in neocortex. Furthermore, the αCaMKII autophosphorylation is essential for contextual long-term memory (LTM) formation after a single training trial but not after a massed training session. Here, we show that in the absence of αCaMKII autophosphorylation contextual fear conditioning is hippocampus dependent and that multi-tetanus-dependent late-LTP cannot be induced in hippocampal area CA1. Furthermore, we show that in the absence of αCaMKII autophosphorylation contextual LTM persists for 30 days, the latest time point tested. Additionally, contextual, but not cued, LTM formation in the absence of αCaMKII autophosphorylation appears to be impaired in 18 month-old mice. Taken together, our findings suggest that αCaMKII autophosphorylation-independent plasticity in the hippocampus is sufficient for contextual LTM formation and that αCaMKII autophosphorylation may be important for delaying age-related impairments in hippocampal memory formation. Furthermore, they propose that NMDA receptor-dependent LTP in hippocampal area CA1 is essential for contextual LTM formation after a single trial but not after massed training. Finally, our results challenge the proposal that NMDA receptor-dependent LTP in neocortex is required for remote contextual LTM.
    Molecular Brain 01/2011; 4(1):8. DOI:10.1186/1756-6606-4-8 · 4.35 Impact Factor
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