Long-Term Potentiation Research Paper

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Since Ramon y Cajal, neurobiologists have been looking for activity-dependent modifications of synaptic efficacy as a potential mechanism for learning and memory. When Bliss went to Per Andersen’s laboratory in 1968, he probably did not know he was going to discover a phenomenon that would become one of the most popular, controversial, and debated one in Neuroscience until the end of the twentieth century. The first publication (Bliss and Lomo 1973), reporting the existence of long-term potentiation (LTP) in rabbit brain, was noticed by only a small number of laboratories. Even the demonstration that LTP could be elicited in the in itro hippocampal slice preparation (Lynch et al. 1977, Andersen et al. 1977) remained somewhat of a curiosity until the end of the 1970s. It was not until the mid-1980s and the identification of the unique properties of the N-Methyl-DAspartate (NMDA) receptors and of the links between LTP and learning and memory (Morris et al. 1986) that LTP began to attract very large numbers of investigators. This review covers the major advances that have taken place since the 1960s, and gives the reader a sense for what is well understood, what remains speculative, and what remains to be understood.

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1. The NMDA Receptor and LTP Induction

The cellular events that are necessary and sufficient to produce LTP are now well understood (Malenka and Nicoll 1999). What is required is sufficient postsynaptic depolarization (i.e., the high frequency bursts of stimulation) to relieve the NMDA receptor channel from a voltage-dependent magnesium blockade and to produce a postsynaptic influx of calcium at the right place and of the right amplitude. The NMDA receptor thus functions as an AND gate (presynaptic release of neurotransmitter and postsynaptic depolarization) and accounts for most features of LTP, such as associativity, calcium dependency, regulation by the degree of inhibition, etc. It should be noted however, that some forms of LTP do not require NMDA receptor activation, and thus there may be multiple forms of LTP as well as multiple ways of triggering the biochemical cascades leading to LTP.

2. The Pre- vs. Post-synaptic Debate

It was clear from the outset that LTP could be due to changes in either the release characteristics of the presynaptic terminals or the postsynaptic responsiveness to the neurotransmitter or some combination of both factors. As some reports suggested that glutamate release is enhanced following LTP induction (Bliss 1990), the postsynaptic localization of NMDA receptors imposed the existence of some retrograde signals that could link LTP induction to LTP expression mechanisms. Several such signals were proposed such as arachidonic acid, nitric oxide (NO), or carbon monoxide (CO) (O’Dell et al. 1991). On the other hand, many reports have also indicated several postsynaptic modifications including changes in the properties of another type of glutamate receptors, the α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors, and in the morphology and number of dendritic spines (Maren et al. 1993; Lee et al. 1980). There is now some general agreement that LTP expression is due to several modifications of the distribution of AMPA receptors and the structure of synaptic contacts (Malenka and Nicoll 1999).

3. The Biochemical Confusion

Since the 1980s, a very large number of biochemical events have been proposed to participate in one way or another in LTP induction or expression (Sanes and Lichtman 1999). Among these, several calcium-dependent processes have been identified. Activation of the calcium-dependent protease, calpain, results in modifications of the structure of several cytoskeletal proteins and cell adhesion molecules and therefore is ideally suited to promote modifications in the structure of synaptic contacts (Baudry 1991). Activation of several protein kinases, and in particular, calcium calmodulin kinase type II (CamKII), is also a key process to phosphorylate key proteins in synaptic contacts, including glutamate receptors (Kennedy 1989). Autophosphorylation of CamKII might also provide for a form of short-term plasticity that exceeds the duration of the LTP-inducing stimulus. Finally, activation of phospholipases provides for both the synthesis of lipid breakdown products with various signaling properties as well as for the breakdown of membrane lipids, an essential element for structural modifications (Massicotte and Baudry 1991). It is interesting to point out that most of these cell biological processes are not unique to neurons but are present in many cell types where they participate in regulation of structure and function.

4. Gene Expression and LTP Stabilization

A much-debated issue in the LTP literature concerns the role of gene expression and protein synthesis and the mechanisms linking LTP induction to the protein synthesis machinery of neurons. Numerous studies have attempted to identify genes activated as a result of LTP induction (Abraham et al. 1993, Thomas et al. 1994). In most cases, several transcription factors are induced as a result of trains of electrical activity producing LTP. However, it has been quite difficult to further establish the relationship between gene induction with mechanisms underlying LTP expression and maintenance.

Advances in molecular biology techniques, and in particular, the possibility of knocking out or knocking in specific genes have produced a large number of mutant mice with various ‘learning and memory’ impairments, in addition to problems with LTP induction or maintenance (Silva et al. 1997). In addition, the mutations that have been generated often affect enzymes, receptor channels, or other cellular elements, which participate in ‘normal’ cellular functions, and are likely to modify, even in a subtle way, various aspects of brain structure and function. The limitation on the role of gene expression in synaptic plasticity resulting from the cell-wide modifications it generally produces would be seriously eliminated if there were mechanisms coupling gene expression and local translation of the corresponding mRNAs. For local protein synthesis to take place requires the dendritic targeting of mRNA and there are now a number of examples of such mRNAs. Furthermore, there is also experimental evidence for links between synaptic transmission and regulation of local protein synthesis as activation of glutamate metabotropic receptors in synaptoneurosomes has been shown to rapidly stimulate protein synthesis (Weiler and Greenough 1993). There are therefore two types of mechanisms by which synaptic activity can produce localized modifications of synaptic properties restricted to activated synapses. In the first one, a small population of mRNAs is constitutively present in dendrites, and in response to an appropriate signal, these mRNAs are locally translated, and the newly synthesized proteins are incorporated into the activated synapses. Note that this process is rapid and does not require gene expression, as it only depends on constitutively present mRNAs. In the second one, some locally generated signals are transmitted to the cell nucleus, trigger gene transcription, and the synthesis of mRNAs. These mRNAs are targeted to the dendrites and locally translated at the appropriate site. Note that this requires the existence of a signal or signals that remain present at activated synapses for quite some time as the transcription of genes, and their targeting to the dendrites necessitate a significant period of time. This mechanism is somewhat related to the synaptic tagging described by Frey and Morris (1998). In their model, these authors propose that LTP induction is accompanied by the activation of signals they call ‘synaptic tags,’ which interact with plasticityrelated newly synthesized proteins and stabilize the formation of long-term potentiation. Clearly, much more work is needed to clarify the exact mechanisms involved in this type of regulation, and to determine the types of mRNAs present in the dendrites, the mechanisms involved in targeting them to dendrites and the signals responsible for tagging activated synapses. Finally, the types of proteins involved and their roles in regulating synaptic structure and function need to be further investigated.

It has only recently been recognized that the extracellular matrix plays an equally important role in regulating synaptic morphology and properties. Antibodies to N-CAM and peptide inhibitors of integrin receptors inhibit the formation of stable long-term potentiation (LTP) (Luthi et al. 1994, Lynch 1998). In several current models of LTP, stabilization of the modifications triggered during the induction phase of LTP is accomplished first by the disruption of the adhesive properties of synaptic contacts, possibly mediated through the proteolysis of CAM molecules, followed by the activation of integrins. In this way, synaptic contacts undergo a cycle of destabilization resulting from intracellular as well as extracellular proteolysis of proteins contributing to the morphology of synaptic contacts, followed by restabilization of a new synaptic structure implicating integrin activation and extracellular matrix components (Lynch 1998).

5. LTP and Learning and Memory

LTP is the most widely proposed mechanism of memory storage in the hippocampus and neocortex. Although this issue is still debated, evidence supporting this hypothesis comes from a variety of experimental data and theoretical models (Baudry and Davis 1996). LTP is prevalent in hippocampal and cortical networks and exhibits many properties required for a large capacity information storage device: rapid induction, associativity, long duration, links with brain rhythms (in particular, the theta rhythm). Pharmacological manipulations or gene mutations interfering with LTP also interfere with various forms of learning and memory, while pharmacological agents facilitating LTP formation also facilitate learning. Finally, incorporating LTP-based rules in biologically realistic neuronal networks produces large capacity storage devices.

6. Conclusions

Much progress has been made on our understanding of the mechanisms and functions of LTP since its discovery in 1968. At the beginning of the twenty-first century there might still be a few unanswered questions, but there is little doubt that (a) these questions will receive definite answers rapidly and (b) the knowledge gained from the study of this phenomenon will be instrumental in designing new tools to study and improve various forms of learning impairments.


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