Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Enhancement of Consolidated Long-Term Memory

 

Science 4 March 2011: Vol. 331 no. 6021 pp. 1207-1210
Enhancement of Consolidated Long-Term Memory by Overexpression of Protein Kinase Mζ in the Neocortex

Reut Shema1, Sharon Haramati1, Shiri Ron1, Shoshi Hazvi1, Alon Chen1, Todd Charlton Sacktor2, and Yadin Dudai1

1Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.

2Departments of Physiology, Pharmacology, and Neurology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA

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Memories are more easily disrupted than improved. Many agents can impair memories during encoding and consolidation. In contrast, the armamentarium of potential memory enhancers is so far rather modest. Moreover, the effect of the latter appears to be limited to enhancing new memories during encoding and the initial period of cellular consolidation, which can last from a few minutes to hours after learning. Here, we report that overexpression in the rat neocortex of the protein kinase C isozyme protein kinase Mζ (PKMζ) enhances long-term memory, whereas a dominant negative PKMζ disrupts memory, even long after memory has been formed.

Amnesic agents impair fresh memories during encoding and consolidation, and some can block reactivated long-term memories at reconsolidation. Furthermore, selective brain lesions result in extensive loss of remote memories. Some agents have been proposed as potential memory enhancers, but their beneficial effect seems to be limited to the encoding and immediate consolidation period. The importance of memory enhancement for treating cognitive decline calls for an intensive exploration of the effect of manipulating components of the memory storage machinery on memory performance.

Protein kinase Mζ (PKMζ) is a persistently active, atypical protein kinase C isoform that is critical for maintaining the storage of long-term memory long after its initial consolidation. We have previously reported that inhibition of PKMζ in the insular cortex (IC) of the behaving rat by the pseudosubstrate zeta inhibitory peptide (ZIP) leads to erasure of long-term memory of conditioned taste aversion (CTA), an associative type of memory, up to at least 3 months after encoding, without affecting the ability of the rat to relearn the same association and without impairing recognition memory. The training itself leads to a persistent increase in the level of the endogenous PKMζ protein in the IC. We wanted to investigate the effect on CTA memory of targeted modulation of the level of PKMζ in the IC.

PKMζ synthesized in neurons is captured at recently active synapses, by a process of synaptic tagging, enabling these specific synapses to maintain a persistent state of enhanced efficacy. Thus, it is plausible to assume that the overexpressed kinase may augment the endogenous increase. We did observe differential accumulation of overexpressed PKMζ in dendritic spines in the IC in vivo, which is consistent with but does not prove the hypothesis. Selectivity resulting in strengthening memory might hence be achieved if the new enzyme molecules synthesized by the overexpressed gene are preferentially attracted to tagged synapses. The enhancement of memory long after encoding also raises the possibility that synaptic tagging and capture can mold memory over much longer periods of time than previously supposed, a mechanism that might be useful in situations such as the integration of new episodic items into long-term memory schemata or, more generally, memory summation over prolonged periods of time.

The observation that overexpression of PKMζ enhances memories long after they had been formed renders it plausible to consider PKMζ a potential target not only for memory blockers (which might be useful, for example, in treating post-traumatic stress) but also for novel types of memory enhancers in the treatment of amnesia and cognitive decline.

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