Review
The substrates of memory: Defects, treatments, and enhancement

https://doi.org/10.1016/j.ejphar.2007.11.082Get rights and content

Abstract

Recent work has added strong support to the long-standing hypothesis that the stabilization of both long-term potentiation and memory requires rapid reorganization of the spine actin cytoskeleton. This development has led to new insights into the origins of cognitive disorders, and raised the possibility that a diverse array of memory problems, including those associated with diabetes, reflect disturbances to various components of the same mechanism. In accord with this argument, impairments to long-term potentiation in mouse models of Huntington's disease and in middle-aged rats have both been linked to problems with modulatory factors that control actin polymerization in spine heads. Complementary to the common mechanism hypothesis is the idea of a single treatment for addressing seemingly unrelated memory diseases. First tests of the point were positive: Brain-Derived Neurotrophic Factor (BDNF), a potent activator of actin signaling cascades in adult spines, rescued potentiation in Huntington's disease mutant mice, middle-aged rats, and a mouse model of Fragile-X syndrome. A similar reversal of impairments to long-term potentiation was obtained in middle-aged rats by up-regulating BDNF production with brief exposures to ampakines, a class of drugs that positively modulate AMPA-type glutamate receptors. Work now in progress will test if chronic elevation of BDNF enhances memory in normal animals.

Introduction

Well over a hundred years ago Ribot proposed that memory is encoded by changes in connections between the brain's ‘nervous elements’ and becomes stabilized (resistant to disruption) during the first several minutes following its acquisition (Ribot, 1882). Confirmation of the first point, and descriptions of how the second might be accomplished, did not come quickly. It was not until 1973, and the advent of long-term potentiation (LTP) (Bliss and Lomo, 1973), that synapses were shown to possess the expected capability for rapid and persistent changes in efficacy. The subsequent discovery that potentiation is vulnerable to disruption for several minutes after induction (Arai et al., 1990, Barrionuevo et al., 1980) endowed LTP with the third member of an unlikely combination of properties required of a memory substrate: synapse specificity, extraordinary stability, and a rapid onset consolidation process. The links to memory were further strengthened by evidence that LTP occurs during learning (Roman et al., 1987) and that agents which block the effect cause amnesia (Morris et al., 1986). As evidence of these types gradually accumulated, a sizeable group of investigators began to use LTP as a surrogate in the search for the cellular processes that encode and consolidate memory.

Efforts to isolate the synaptic events responsible for various aspects of LTP have accelerated in recent years, in part because of new technologies and in part because of past successes in sharpening the focus of the search. Increasing attention is now being given to the possibility of using the growing body of information about LTP to investigate the causes of, and potential treatments for, various memory and cognitive disorders. Related to this are LTP-based projects concerned with the design of memory enhancing drugs (Lynch, 2002). In the following sections we will consider these developments beginning with new evidence on the synaptic processes that express and stabilize LTP.

Section snippets

Substrates of LTP

Experiments showing that the induction of LTP requires increases in dendritic calcium concentrations (Lynch et al., 1983) led to the early assumption that potentiation is expressed by a post-synaptic change, most probably to the number of glutamate receptors (Lynch and Baudry, 1984). That LTP is accompanied by ultrastructural changes to the post-synaptic density (Chang and Greenough, 1984, Desmond and Levy, 1986, Geinisman et al., 1993, Harris et al., 2003, Lee et al., 1980, Yuste and

LTP-related changes to spines and synapses occur during learning

The above results describe mechanisms that could potentially encode and stabilize memory: they are associated with a change in synaptic strength, occur quickly in a synapse-specific fashion, and contribute to a structural modification. We tested for their occurrence during learning using an unsupervised paradigm in which young adult rats gain familiarity with a complex environment (Fedulov et al., 2007). The animals were handled extensively over a five day period and then placed into one of

A common target for diseases of memory?

The above results, combined with other findings not discussed here, can be assembled into a reasonably specific hypothesis about the formation of memory (Fig. 4). The argument begins with the presence of three quite different classes of receptors in the synapse: a) transmitter, b) adhesion, and c) modulatory. A very substantial body of work indicates that LTP consolidation (but not induction and expression) requires signaling from adhesion receptors belonging to the integrin family (Gall and

Treating learning-related defects in cytoskeletal plasticity

The above sections describe evidence that changes to the spine cytoskeleton consolidate LTP and that similar events occur during the formation of stable memory. Results were also summarized suggesting that defects in these LTP/learning processes are found in mouse models of three different human conditions involving disturbances to memory and cognition. The question now arises as to whether it will be possible to use this information to design novel therapeutics. One possibility in this

Consolidation

The idea that the extreme persistence of LTP reflects changes to spine anatomy, and thus to the spine cytoskeleton, was advanced during the early years of LTP research (Lee et al., 1980, Lynch and Baudry, 1984, Matus, 2000). The recent work described here provides strong evidence in support of the hypothesis. Threshold levels of theta burst stimulation, an experimental treatment that produces the type of synapse-specific potentiation assumed to be responsible for memory in big-brained mammals,

Acknowledgements

This work was supported in part by NINDS grants NS045260, NS051823 and NS37799. C.S. Rex was supported by National Institutes of Aging grant AG00258.

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