Novel insights into CaMKII function and regulation during memory formation

Lucchesi, Walter; Mizuno, Keiko; Giese, K. Peter

doi:10.1016/j.brainresbull.2010.10.009

Cited by 87 publications

(69 citation statements)

References 84 publications

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“…The role of CaMKII-dependent processes in consolidation has been amply documented (32)(33)(34)(35), including the consolidation of the extinction of inhibitory avoidance learning (34). For that reason, the lack of effect of AIP on CFC extinction was surprising (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

Myskiw

Furini

Benetti

et al. 2014

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

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Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by β-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-andcapture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.hippocampus | memory | synaptic tagging and capture | synaptic plasticity | fear conditioning F rey and Morris (1, 2) and their collaborators (3-7) proposed a mechanism whereby relatively "weak" hippocampal longterm potentiation (LTP) or long-term depression (LTD) lasting only a few minutes can nevertheless "tag" the synapses involved with proteins synthesized ad hoc, so that other plasticity-related proteins (PRPs) produced at other sets of synapses by other LTPs or LTDs can be captured by the tagged synapses and strengthen their activity to "long" LTPs or LTDs lasting hours or days (8). LTDs and LTPs can "cross"-tag each other; that is, LTDs can enhance both LTDs and LTPs, and vice versa (6,8). Because many learned behaviors rely on hippocampal LTP or LTD (7-9), among them the processing of novelty (9, 10) and the making of extinction (11-13), interactions between consecutive learnings can also be explained by the "tagging-and-capture" hypothesis (9, 10, 13), whose application to behavior became known as "behavioral tagging and capture" (5, 7, 9, 13). Typically, exposure to a novel environment [e.g., a nonanxiogenic 50 × 50 × 40-cm open field (OF) (5,7,9,10,14)] is interpolated before testing for another task, which becomes enhanced (4-10, 13). The usual reaction to novelty is orienting and exploration (14), followed by habituation of this response (14-16). Habituation is perhaps the simplest form of learning, and it consists of inhibition of the orienting/exploratory response (14, 16).We recently showed that the brief exposure of rats to a novel environment (the OF) within a limited time window enhances the extinction of contextual fear conditioning (CFC) through a mechanism of synaptic tagging and capture (13), which is a previously unidentified example of behavioral tagging of inhibitory lea...

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Section: Discussionmentioning

confidence: 99%

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

Myskiw

Furini

Benetti

et al. 2014

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

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“…To further explore the mechanism underlying the improvement in memory function and spine formation, we analyzed the levels of phosphorylation of calcium/calmodulin-dependent protein kinase II (pCaMKII; Thr286) and of extracellular signal-related kinase 1/2 (pERK1/2) that may also promote synaptic plasticity (Giese and Mizuno, 2013;Lucchesi et al, 2011;Vaillant et al, 2002). A significant increase was observed in the case of pCaMKII levels with no effects on pERK1/2 in the group of mice treated with CM-414 (Figure 4f).…”

Section: Effects Of Cm-414 On Pathological Markers Of Ad In Aged-tg25mentioning

confidence: 99%

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Cuadrado‐Tejedor

García‐Barroso

Sánchez‐Arias

et al. 2016

Neuropsychopharmacol

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The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

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“…1). Accordingly, CaMKII activity is increased during memory formation (e.g., Cammarota et al 1998) and blockade of CaMKII substantially impairs memory formation (for reviews, see Lisman et al 2002;Elgersma et al 2004;Irvine et al 2006;Wayman et al 2008;Lucchesi et al 2011;Coultrap and Bayer 2012). This indicates that CaMKII has an essential function in memory formation.…”

Section: Camkiimentioning

confidence: 99%

The roles of protein kinases in learning and memory

2013

Self Cite

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In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate gene expression and protein synthesis causing structural changes at existing synapses as well as synaptogenesis. Here, we review the roles of these kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. Specifically, we discuss the roles of calcium/calmodulin-dependent kinase II (CaMKII

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Novel insights into CaMKII function and regulation during memory formation

Cited by 87 publications

References 84 publications

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

The roles of protein kinases in learning and memory

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