Lledo PM, Hjelmstad GO, Mukherji S, Soderling TR, Malenka RC, Nicoll RA. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc Natl Acad Sci USA 92: 11175-11179

Department of Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0450, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/1995; 92(24):11175-9. DOI: 10.1073/pnas.92.24.11175
Source: PubMed


Ca(2+)-sensitive kinases are thought to play a role in long-term potentiation (LTP). To test the involvement of Ca2+/calmodulin-dependent kinase II (CaM-K II), truncated, constitutively active form of this kinase was directly injected into CA1 hippocampal pyramidal cells. Inclusion of CaM-K II in the recording pipette resulted in a gradual increase in the size of excitatory postsynaptic currents (EPSCs). No change in evoked responses occurred when the pipette contained heat-inactivated kinase. The effects of CaM-K II mimicked several features of LTP in that it caused a decreased incidence of synaptic failures, an increase in the size of spontaneous EPSCs, and an increase in the amplitude of responses to iontophoretically applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. To determine whether the CaM-K II-induced enhancement and LTP share a common mechanism, occlusion experiments were carried out. The enhancing action of CaM-K II was greatly diminished by prior induction of LTP. In addition, following the increase in synaptic strength by CaM-K II, tetanic stimulation failed to evoke LTP. These findings indicate that CaM-K II alone is sufficient to augment synaptic strength and that this enhancement shares the same underlying mechanism as the enhancement observed with LTP.

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    • "For instance, whereas the necessity of postsynaptic calcium elevation for the induction of long-term potentiation (LTP) was established using calcium chelators (Lynch et al. 1983), the sufficiency of calcium for inducing LTP was later demonstrated using postsynaptic uncaging of calcium (Malenka et al. 1988). Similarly, turning to the involvement of calcium/ calmodulin-activated kinase II (CaMKII) in LTP, specific CaMKII inhibitors were employed to show that CaMKII was necessary for the induction of LTP (Otmakhov et al. 1997), whereas the sufficiency of CaMKII in inducing LTP was revealed by injecting constitutively active CaMKII using patch micropipettes (Lledo et al. 1995). In this context, it was recently demonstrated that InsP 3 Rs are necessary for the induction of plasticity of intrinsic response dynamics that is consequent to calcium store depletion (Narayanan et al. 2010). "
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    ABSTRACT: The synaptic plasticity literature has focused on establishing necessity and sufficiency as two essential and distinct features in causally relating a signaling molecule to plasticity induction, an approach that has been surprisingly lacking in the intrinsic plasticity literature. Here, we complemented the recently established necessity of inositol trisphosphate (InsP3) receptors (InsP3R) in a form of intrinsic plasticity by asking if InsP3R activation was sufficient to induce intrinsic plasticity in hippocampal neurons. Specifically, incorporation of D-myo-InsP3 in the recording pipette reduced input resistance, maximal impedance amplitude and temporal summation, but increased resonance frequency, resonance strength, sag ratio, and impedance phase lead. Strikingly, the magnitude of plasticity in all these measurements was dependent upon [InsP3], emphasizing the graded dependence of such plasticity on InsP3R activation. Mechanistically, we found that this InsP3-induced plasticity depended on hyperpolarization-activated cyclic-nucleotide gated channels. Moreover, this calcium-dependent form of plasticity was critically reliant on the release of calcium through InsP3Rs, the influx of calcium through N-methyl-D-aspartate receptors and voltage-gated calcium channels, and on the protein kinase A pathway. Our results delineate a causal role for InsP3Rs in graded adaptation of neuronal response dynamics, revealing novel regulatory roles for the endoplasmic reticulum in neural coding and homeostasis. Copyright © 2014, Journal of Neurophysiology.
    Journal of Neurophysiology 12/2014; 113(7):jn.00833.2014. DOI:10.1152/jn.00833.2014 · 2.89 Impact Factor
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    • "Numerous signal transduction pathways were suggested to play a role in translating the calcium signal into LTP (Sanes and Lichtman, 1999; Malenka and Bear, 2004). Compelling evidence using genetic and pharmacological approaches indicated that calcium/calmodulin (CaM)-dependent protein kinase II (CaMKII) played a mandatory role in longlasting increase of synaptic strength (Malenka et al., 1988; Malinow et al., 1989; Silva et al., 1992; Pettit et al., 1994; Lledo et al., 1995, 1998; Giese et al., 1998; Lisman et al., 2012). Due to the prominent role of CaMKII in LTP, it was initially assumed that AMPARs insertion was only indirectly regulated by calcium, in contrast to the calcium-regulated exocytosis observed in the presynaptic terminal. "
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    ABSTRACT: Sorting endosomes carry α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) from their maturation sites to their final destination at the dendritic plasma membrane through both constitutive and regulated exocytosis. Insertion of functional AMPARs into the postsynaptic membrane is essential for maintaining fast excitatory synaptic transmission and plasticity. Despite this crucial role in neuronal function, the machinery mediating the fusion of AMPAR-containing endosomes in dendrites has been largely understudied in comparison to presynaptic vesicle exocytosis. Increasing evidence suggests that similarly to neurotransmitter release, AMPARs insertion relies on the formation of a SNARE complex (soluble NSF-attachment protein receptor), whose composition in dendrites has just begun to be elucidated. This review analyzes recent findings of the fusion machinery involved in regulated AMPARs insertion and discusses how dendritic exocytosis and AMPARs lateral diffusion may work together to support synaptic plasticity.
    Frontiers in Cellular Neuroscience 12/2014; 8:407. DOI:10.3389/fncel.2014.00407 · 4.29 Impact Factor
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    • "Conversely, the injection or viral expression of a constitutively active form of CaMKII leads to the improvement of spatial memory (Poulsen et al. 2007), in enhancement of AMPAR-mediated synaptic transmission and occludes further induction of LTP (McGlade- McCulloh et al. 1993; Pettit et al. 1994; Lledo et al. 1995). This enhancement in AMPAR conductance has been proposed to occur through an increase in synaptic trafficking of GluA1 subunits, as well as phosphorylation of GluA1 at Ser831 (Shi et al. 1999; Hayashi et al. 2000; Broutman and Baudry 2001; Esteban et al. 2003; Oh et al. 2006). "
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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 · 3.66 Impact Factor
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