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Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression
Shunsuke Hasegawa, Takahiro Furuichi, Taro Yoshida, Kengo Endoh, Kenichi Kato, Megumi Sado, Ryouta Maeda, Aya Kitamoto, Takahisa Miyao, Ryosuke Suzuki, Seiichi Homma, Shoichi Masushige, Yasushi Kajii, Satoshi Kida
Molecular Brain , 2009, DOI: 10.1186/1756-6606-2-6
Abstract: We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression.Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.Alpha-CaMKII is a Ser/Thr protein kinase that is abundantly expressed in the forebrain [1-5]. In response to an increase in the intracellular concentration of Ca2+, alpha-CaMKII is activated through the binding of Ca2+/calmodulin (CaM), and then phosphorylates target proteins to activate or inactivate these proteins [1-5]. Furthermore, the prolonged activation of alpha-CaMKII by Ca2+/CaM results in the intramolecular autophosphorylation of Thr residues such as T286, T305, and T306 [1-5]. Autophosphorylation of T286 leads to a decrease in the dissociation of bound Ca2+/CaM and continuous partial activation even after the dissociation of Ca2+/CaM, thereby prolonging its activation. Thus, a transient increase in intracellula
CaMKII Binding to GluN2B Is Differentially Affected by Macromolecular Crowding Reagents  [PDF]
Dayton J. Goodell, Tatiana A. Eliseeva, Steven J. Coultrap, K. Ulrich Bayer
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096522
Abstract: Binding of the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B controls long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. Regulation of this interaction is well-studied biochemically, but not under conditions that mimic the macromolecular crowding found within cells. Notably, previous molecular crowding experiments with lysozyme indicated an effect on the CaMKII holoenzyme conformation. Here, we found that the effect of molecular crowding on Ca2+/CaM-induced CaMKII binding to immobilized GluN2B in vitro depended on the specific crowding reagent. While binding was reduced by lysozyme, it was enhanced by BSA. The ATP content in the BSA preparation caused CaMKII autophosphorylation at T286 during the binding reaction; however, enhanced binding was also observed when autophosphorylation was blocked. Importantly, the positive regulation by nucleotide and BSA (as well as other macromolecular crowding reagents) did not alleviate the requirement for CaMKII stimulation to induce GluN2B binding. The differential effect of lysozyme (14 kDa) and BSA (66 kDa) was not due to size difference, as both dextran-10 and dextran-70 enhanced binding. By contrast, crowding with immunoglobulin G (IgG) reduced binding. Notably, lysozyme and IgG but not BSA directly bound to Ca2+/CaM in an overlay assay, suggesting a competition of lysozyme and IgG with the Ca2+/CaM-stimulus that induces CaMKII/GluN2B binding. However, lysozyme negatively regulated binding even when it was instead induced by CaMKII T286 phosphorylation. Alternative modes of competition would be with CaMKII or GluN2B, and the negative effects of lysozyme and IgG indeed also correlated with specific or non-specific binding to the immobilized GluN2B. Thus, the effect of any specific crowding reagent can differ, depending on its additional direct effects on CaMKII/GluN2B binding. However, the results of this study also indicate that, in principle, macromolecular crowding enhances CaMKII binding to GluN2B.
CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning  [PDF]
John M. Gillespie,James J. L. Hodge
Frontiers in Molecular Neuroscience , 2013, DOI: 10.3389/fnmol.2013.00027
Abstract: Calcium (Ca2+)/calmodulin (CaM)-dependent kinase II (CaMKII) activity plays a fundamental role in learning and memory. A key feature of CaMKII in memory formation is its ability to be regulated by autophosphorylation, which switches its activity on and off during synaptic plasticity. The synaptic scaffolding protein CASK (calcium (Ca2+)/calmodulin (CaM) associated serine kinase) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. We show that in Drosophila larvae, CASK interacts with CaMKII to control neuronal growth and calcium signaling. Furthermore, deletion of the CaMK-like and L27 domains of CASK (CASK β null) or expression of overactive CaMKII (T287D) produced similar effects on synaptic growth and Ca2+ signaling. CASK overexpression rescues the effects of CaMKII overactivity, consistent with the notion that CASK and CaMKII act in a common pathway that controls these neuronal processes. The reduction in Ca2+ signaling observed in the CASK β null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca2+ signaling in CASK mutants was associated with an increase in Ether-à-go-go (EAG) potassium (K+) channel localization to synapses. Reducing EAG restored the decrease in Ca2+ signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca2+ signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca2+ responses in Drosophila mushroom bodies, which are the learning centers of Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation.
CASK and CaMKII function in the mushroom body α′/β′ neurons during Drosophila memory formation  [PDF]
John Michael Gillespie,James J. L. Hodge
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2013.00052
Abstract: Ca2+/CaM serine/threonine kinase II (CaMKII) is a central molecule in mechanisms of synaptic plasticity and memory. A vital feature of CaMKII in plasticity is its ability to switch to a calcium (Ca2+) independent constitutively active state after autophosphorylation at threonine 287 (T287). A second pair of sites, T306 T307 in the calmodulin (CaM) binding region once autophosphorylated, prevent subsequent CaM binding and inactivates the kinase during synaptic plasticity and memory. Recently a synaptic molecule called Ca2+/CaM-dependent serine protein kinase (CASK) has been shown to control both sets of CaMKII autophosphorylation events and hence is well poised to be a key regulator of memory. We show deletion of full length CASK or just its CaMK-like and L27 domains disrupts middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α′/β′ subset of mushroom body neurons being required for memory. Likewise directly changing the levels of CaMKII autophosphorylation in these neurons removed MTM and LTM. The requirement of CASK and CaMKII autophosphorylation was not developmental as their manipulation just in the adult α′/β′ neurons was sufficient to remove memory. Overexpression of CASK or CaMKII in the α′/β′ neurons also occluded MTM and LTM. Overexpression of either Drosophila or human CASK in the α′/β′ neurons of the CASK mutant completely rescued memory, confirming that CASK signaling in α′/β′ neurons is necessary and sufficient for Drosophila memory formation and that the neuronal function of CASK is conserved between Drosophila and human. At the cellular level CaMKII overexpression in the α′/β′ neurons increased activity dependent Ca2+ responses while reduction of CaMKII decreased it. Likewise reducing CASK or directly expressing a phosphomimetic CaMKII T287D transgene in the α′/β′ similarly decreased Ca2+ signaling. Our results are consistent with CASK regulating CaMKII autophosphorylation in a pathway required for memory formation that involves activity dependent changes in Ca2+ signaling in the α′/β′ neurons.
Properties of Contextual Memory Formed in the Absence of αCaMKII Autophosphorylation
Elaine E Irvine, Arthur Danhiez, Kasia Radwanska, Charlotte Nassim, Walter Lucchesi, Emile Godaux, Laurence Ris, K Giese
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-8
Abstract: A major goal in neuroscience is to understand the molecular and cellular mechanisms underlying learning and memory. Synaptic plasticity, in particular NMDA receptor-dependent long-term potentiation (LTP), is thought to be an important cellular mechanism of memory formation that can be induced by behavioral training [1-4]. An essential signaling molecule downstream of NMDA receptor activation is the alpha-isoform of calcium/calmodulin-dependent protein kinase II (αCaMKII), the major post-synaptic density protein in the hippocampus [5]. After activation αCaMKII can autophosphorylate at threonine-286 (T286), switching the kinase into a calcium/calmodulin-independent, autonomous activity state. This T286 autophosphorylation is essential for NMDA receptor-dependent LTP at excitatory synapses in hippocampal area CA1 and neocortex, as indicated by studies with αCaMKII autophosphorylation-deficient knockin (αCaMKIIT286A) mice [6-9].Hippocampal area CA1 is essential for memory formation after contextual fear conditioning, a task in which a rodent learns to associate a neutral environment (context) with an aversive foot shock [10,11]. The αCaMKIIT286A mutant mice have impaired contextual fear long-term memory (LTM) formation after a single training trial or a massed session of 3 trials [12]. However, unexpectedly αCaMKIIT286A mutants can form contextual LTM after a massed training session of 5 trials [12]. This finding posed several mechanistic questions, which we have addressed here. We studied whether a) short-term memory (STM) formation depends on αCaMKII autophosphorylation in the same way as LTM formation, b) spaced training also enables contextual LTM formation without αCaMKII autophosphorylation, c) contextual LTM formation in the absence of αCaMKII autophosphorylation requires the hippocampus, d) multiple tetani can induce L-LTP in hippocampal area CA1 in the absence of αCaMKII autophosphorylation, e) remote contextual LTM requires αCaMKII autophosphorylation, f) LTM
Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia
Feng Wei, Guo-Du Wang, Chao Zhang, Kevan M Shokat, Huimin Wang, Joe Z Tsien, Jason Liauw, Min Zhuo
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-21
Abstract: Ca2+/calmodulin-dependent kinase II (CaMKII) is a key molecule involved in regulating glutamatergic synaptic transmission and learning and memory [1,2]. Several lines of evidence support a role for CaMKII in synaptic plasticity and memory (see [2] for review). The ability of CaMKII to autophosphorylate, which prolongs activation in a CaM independent manner, supports an important role for CaMKII in synaptic plasticity [2]. A point mutation in the CaMKII gene that blocks autophosphorylation abolished LTP and impaired spatial memory in mice [3]. While the autophosphorylation and dephosphorylation of CaMKII support the hypothesis that it can act as a "molecular switch" in plasticity and memory, recent studies favor a more sophisticated frequency-dependent biphasic modulation of CaMKII in learning-related synapses. Transgenic mice that overexpress a calcium independent form of CaMKII in forebrain areas demonstrated a shift of frequency-dependent responses to repetitive stimulation [4]. Consistently, these mice displayed an impairment in spatial memory [5]. The role of CaMKII in central synaptic plasticity is not limited to the hippocampus and spatial memory. In the cortex, αCaMKII activity plays a role in long-term or permanent memory and cortical LTP [6,7].Glutamatergic synapses involved in sensory transmission can undergo learning-like plastic changes [8-11]. Long-term changes in plasticity along sensory transmission pathways, including the spinal cord dorsal horn and cortical neurons, have been reported [12,13]. A role for CaMKII in experience-dependent plasticity was shown in the spinal cord dorsal horn, and spinal CaMKII is involved in the development of persistent pain [14,15]. However, no study has determined if forebrain CaMKII plays a role in the development of persistent pain. The present study takes advantage of recently developed CaMKII transgenic mice that use genetic and chemical techniques to spatially and temporally restrict the expression of CaMKII [16],
Improving a Natural CaMKII Inhibitor by Random and Rational Design  [PDF]
Steven J. Coultrap,K. Ulrich Bayer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025245
Abstract: CaM-KIIN has evolved to inhibit stimulated and autonomous activity of the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) efficiently, selectively, and potently (IC50 ~100 nM). The CN class of peptides, derived from the inhibitory region of CaM-KIIN, provides powerful new tools to study CaMKII functions. The goal of this study was to identify the residues required for CaMKII inhibition, and to assess if artificial mutations could further improve the potency achieved during evolution.
Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation  [PDF]
Peter Rellos,Ashley C. W. Pike,Frank H. Niesen,Eidarus Salah,Wen Hwa Lee,Frank von Delft,Stefan Knapp
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000426
Abstract: Long-term potentiation (LTP), a long-lasting enhancement in communication between neurons, is considered to be the major cellular mechanism underlying learning and memory. LTP triggers high-frequency calcium pulses that result in the activation of Calcium/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKII acts as a molecular switch because it remains active for a long time after the return to basal calcium levels, which is a unique property required for CaMKII function. Here we describe the crystal structure of the human CaMKIIδ/Ca2+/CaM complex, structures of all four human CaMKII catalytic domains in their autoinhibited states, as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIδ/Ca2+/CaM complex, the inhibitory region adopted an extended conformation and interacted with an adjacent catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix αD. The structural data, together with biophysical interaction studies, reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules.
Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation  [PDF]
Peter Rellos equal contributor,Ashley C. W. Pike equal contributor,Frank H. Niesen,Eidarus Salah,Wen Hwa Lee,Frank von Delft,Stefan Knapp
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000426
Abstract: Long-term potentiation (LTP), a long-lasting enhancement in communication between neurons, is considered to be the major cellular mechanism underlying learning and memory. LTP triggers high-frequency calcium pulses that result in the activation of Calcium/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKII acts as a molecular switch because it remains active for a long time after the return to basal calcium levels, which is a unique property required for CaMKII function. Here we describe the crystal structure of the human CaMKIIδ/Ca2+/CaM complex, structures of all four human CaMKII catalytic domains in their autoinhibited states, as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIδ/Ca2+/CaM complex, the inhibitory region adopted an extended conformation and interacted with an adjacent catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix αD. The structural data, together with biophysical interaction studies, reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the Web plugin are available in Text S1.
STDP in a Bistable Synapse Model Based on CaMKII and Associated Signaling Pathways  [PDF]
Michael Graupner ,Nicolas Brunel
PLOS Computational Biology , 2007, DOI: 10.1371/journal.pcbi.0030221
Abstract: The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca2+ concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca2+ levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes.
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