Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.

Lledo, Pierre-Marie; Hjelmstad, Gregory O.; Mukherji, Sucheta; Soderling, Thomas R.; Malenka, Robert C.; Nicoll, Roger A.

doi:10.1073/pnas.92.24.11175

Cited by 413 publications

(250 citation statements)

References 33 publications

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“…The authors attributed this change to a shift toward reduced cortical excitability and an enhanced inhibitory drive in the model of Rett syndrome, rather than to any intrinsic anomaly in the neurons themselves. 125 Ca þ 2 /calmodulin-dependent protein kinase II (CaMKII) is an important mediator of LTP [126][127][128][129][130] and other forms of synaptic plasticity. 131 Stimuli that induce LTP also persistently activate CaMKII, which may be critical for the molecular memory of synaptic events.…”

Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Section: Mouse Models Of Genetic Clinical Disorders With Autism Symptmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…In particular, this kinase is widely believed to be a critical mediator of long term potentiation (LTP), a cellular mechanism that is thought to underlie learning and memory (Bliss and Collingridge, 1993). Several studies have demonstrated that CaMKII is necessary for the induction of LTP (Malinow et al, 1989;Malenka et al, 1989;Silva et al, 1992;Giese et al, 1998), and that introduction of activated CaMKII is sufficient to potentiate synaptic responses in neurons (Pettit et al, 1994;Lledo et al, 1995;McGlade-McCulloh et al, 1993). CaMKII is enriched at the postsynaptic density (PSD) (Kennedy et al, 1983;Suzuki et al, 1994;Petersen et al, 2003), a protein-dense specialization at the post-synaptic membrane that is composed primarily of scaffolding proteins, ion channels, and signal transduction enzymes (Ziff, 1997).…”

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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“…CaMKII␣ knockout mice show impaired hippocampal long term potentiation, a cellular model for learning and memory (12). Conversely, introduction of CaMKII␣ into neurons augments postsynaptic responses and occludes further electrically induced long term potentiation (13,14).CaMKII␣ undergoes calcium/calmodulin-dependent autophosphorylation on Thr 286 in its regulatory domain, rendering the kinase partially calcium-independent (1, 2). This reaction has been proposed as a "molecular switch," translating transient calcium elevation into prolonged kinase activity (15, 16), which becomes subject to regulation by protein phosphatases.…”

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confidence: 99%

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confidence: 99%

Translocation of Autophosphorylated Calcium/Calmodulin-dependent Protein Kinase II to the Postsynaptic Density

Strack

Choi

Lovinger

et al. 1997

Journal of Biological Chemistry

280

236

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Calcium/calmodulin-dependent protein kinase II (CaMKII) undergoes calcium-dependent autophosphorylation, generating a calcium-independent form that may serve as a molecular substrate for memory. Here we show that calcium-independent CaMKII specifically binds to isolated postsynaptic densities (PSDs), leading to enhanced phosphorylation of many PSD proteins including the ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-type glutamate receptor. Furthermore, binding to PSDs changes CaMKII from a substrate for protein phosphatase 2A to a protein phosphatase 1 substrate. Translocation of CaMKII to PSDs occurs in hippocampal slices following treatments that induce CaMKII autophosphorylation and a form of long term potentiation. Thus, synaptic activation leads to accumulation of autophosphorylated, activated CaMKII in the PSD. This increases substrate phosphorylation and affects regulation of the kinase by protein phosphatases, which may contribute to enhancement of synaptic strength.CaMKII 1 isoforms comprise a family of broad specificity, calcium-activated kinases (1, 2). The ␣ and ␤ isoforms are abundantly expressed in the brain, with ␣ making up as much as 2% of total protein in certain brain regions (3). CaMKII is particularly enriched in PSDs (4, 5), cytoskeletal specializations apposed to the postsynaptic membrane of excitatory synapses that are thought to be scaffolds for neurotransmitter receptors, ion channels, and their postsynaptic modulators and effectors (reviewed in Refs. 6 and 7). Earlier reports suggested that CaMKII␣ constitutes as much as 50% of total PSD protein (8 -10), but PSDs prepared from rapidly homogenized brains are only 2-3-fold enriched in CaMKII␣ compared with whole forebrain extracts (3,11). CaMKII␣ knockout mice show impaired hippocampal long term potentiation, a cellular model for learning and memory (12). Conversely, introduction of CaMKII␣ into neurons augments postsynaptic responses and occludes further electrically induced long term potentiation (13,14).CaMKII␣ undergoes calcium/calmodulin-dependent autophosphorylation on Thr 286 in its regulatory domain, rendering the kinase partially calcium-independent (1, 2). This reaction has been proposed as a "molecular switch," translating transient calcium elevation into prolonged kinase activity (15, 16), which becomes subject to regulation by protein phosphatases. (19).Isolation of PSDs-PSDs were prepared from adult rat forebrains flash frozen within 45 s of euthanasia by detergent lysis of synaptosomes (20) except that 1 mM dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 1 mM benzamidine, and 10 g/ml leupeptin were included in all buffers. Synaptosomes were lysed in 1% (v/v) Triton X-100 and 150 mM KCl, and a second subsequent sucrose gradient was omitted because it yielded no further purification. PSDs displayed typical "donut" morphology by video-enhanced differential-interference contrast microscopy (21). PSDs prepared in the absence or the presence of the protein phosphatase inhibitor microcystin-LR (1 M) contained ...

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Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.

Abstract: Ca2+-sensitive kinases are thought to play a role in long-term potentiation (LTP

Cited by 413 publications

References 33 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

αCaMKII autophosphorylation levels differ depending on subcellular localization

Translocation of Autophosphorylated Calcium/Calmodulin-dependent Protein Kinase II to the Postsynaptic Density

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