Rapid Erasure of Long-Term Memory Associations in the Cortex by an Inhibitor of PKM

Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Science (Impact Factor: 33.61). 09/2007; 317(5840):951-3. DOI: 10.1126/science.1144334
Source: PubMed

ABSTRACT Little is known about the neuronal mechanisms that subserve long-term memory persistence in the brain. The components of the remodeled synaptic machinery, and how they sustain the new synaptic or cellwide configuration over time, are yet to be elucidated. In the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, protein kinase M zeta (PKMzeta). The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form.

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    • "The present results add to the accumulating evidence that PKMζ plays crucial roles in the persistence of long - term memory and long - term synaptic plasticity in both vertebrates and invertebrates ( Drier et al . , 2002 ; Ling et al . , 2002 ; Serrano et al . , 2005 ; Pastalkova et al . , 2006 ; Shema et al . , 2007 ) ."
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    ABSTRACT: It has been shown that a variety of long-term memories in different regions of the brain and in different species are quickly erased by local inhibition of PKMζ. Using antibodies to mammalian PKMζ, we describe in the present study the localization of immunoreactive molecules in the nervous system of the terrestrial snail Helix lucorum. Presence of a homologue of PKMζ was confirmed with transcriptomics. We have demonstrated in behavioral experiments that contextual fear memory disappeared under a blockade of PKMζ with a selective peptide blocker of PKMζ (ZIP), but not with scrambled ZIP. If ZIP was combined with a “reminder” (20 min in noxious context), no impairment of the long-term contextual memory was observed. In electrophysiological experiments we investigated whether PKMζ takes part in the maintenance of long-term facilitation (LTF) in the neural circuit mediating tentacle withdrawal. LTF of excitatory synaptic inputs to premotor interneurons was induced by high-frequency nerve stimulation combined with serotonin bath applications and lasted at least four hours. We found that bath application of 2x10-6 M ZIP at the 90th min after the tetanization reduced the EPSP amplitude to the non-tetanized EPSP values. Applications of the scrambled ZIP peptide at a similar time and concentration didn't affect the EPSP amplitudes. In order to test whether effects of ZIP are specific to the synapses, we performed experiments with LTF of somatic membrane responses to local glutamate applications. It was shown earlier that serotonin application in such an "artificial synapse" condition elicits LTF of responses to glutamate. It was found that ZIP had no effect on LTF in these conditions, which may be explained by the very low concentration of PKMζ molecules in somata of these identified neurons, as evidenced by immunochemistry. Obtained results suggest that the Helix homologue of PKMζ might be involved in post-induction maintenance of long-term changes in the snail.
    Frontiers in Cellular Neuroscience 06/2015; 9:222. DOI:10.3389/fncel.2015.00222 · 4.29 Impact Factor
    • "In two recent experiments, conventional and conditional knockout animals have been found to have seemingly normal L-LTP (Volk et al. 2013), and conventional knockout animals displayed normal memory (Lee et al. 2013; Volk et al. 2013). These results stand in apparent contradiction to a plethora of previous experimental results using ZIP and other inhibitors, dominant negative mutations, and overexpression strategies (Drier et al. 2002; Ling et al. 2002; Serrano et al. 2005; Shema et al. 2007, 2009; Migues et al. 2010; Cai et al. 2011; Barry et al. 2012; Ho et al. 2012; Kwapis et al. 2012). Strikingly, ZIP was still able to reverse LTP and erase long-term memory in the constitutive knockout. "
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    ABSTRACT: Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMζ and PKCι/λ, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated. © 2015 Jalil et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 06/2015; 22(7). DOI:10.1101/lm.038844.115 · 3.66 Impact Factor
    • "It is also possible to intervene at later stages: During the labile phase upon recall, reconsolidation could be impaired or prevented (Pitman 2011; Parsons and Ressler 2013). In animal studies, blockade of both consolidation and reconsolidation has been repeatedly demonstrated by inhibiting protein synthesis in memory-related brain regions (Dudai 1996; McGaugh 2000; Nader at al. 2000; Alberini et al. 2006; Shema et al. 2007; Sacktor 2008). In humans, reconsolidation of episodic memory has been disrupted, e.g., through emotionally aversive stimuli or electroconvulsive therapy applied immediately after retrieval (Strange et al. 2010, Kroes et al. 2014). "
    Springer Handbook of Neuroethics, Edited by Jens Clausen & Neil Levy, 01/2015: pages 25; Springer.
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