Copyright © 1999 Massachusetts Institute of Technology
Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy in response to high-frequency stimulation of afferent fibers. The increase in synaptic efficacy persists from minutes to days and is thus a robust example of a long-term increase in synaptic strength. LTP was first observed in the rabbit hippocampus (Bliss and Lomo 1973), but has since been observed in numerous brain structures, including the cortex, brain stem, and amygdala. LTP is not limited to the mammalian brain, but occurs in other vertebrates such as fish, frogs, birds, and reptiles, as well as in some invertebrates (Murphy and Glanzman 1997).
LTP occurs at all three major synaptic connections in the HIPPOCAMPUS: the perforant path synapse to dentate gyrus granule cells, mossy fibers to CA3 pyramidal cells, and the Schaffer collaterals of CA3 cells to CA1 pyramidal cells. Based on its prevalence and initial discovery there, LTP is most often studied in the hippocampus. Within the hippocampus, the cellular and molecular mechanisms that underlie the induction and expression of LTP are varied. In the dentate gyrus and area CA1, the induction of LTP occurs through activation of the postsynaptic N-methyl-D-aspartate (NMDA) type of glutamate receptor and consequent calcium influx (Collingridge, Kehl, and McLennan 1983), while its expression is accompanied by an increase in postsynaptic current mediated by the AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) type of glutamate receptor. In contrast, the induction of mossy fiber LTP in area CA3 is not dependent on NMDA receptor activation, but is dependent on an increase in presynaptic glutamate release (Castillo et al. 1997).
A primary focus of those involved in LTP research is to elucidate the cellular and molecular mechanisms necessary for sustaining the increase in synaptic efficacy over long periods of time. Most of these studies are conducted in neural tissue that is excised and maintained in an in vitro slice environment for physiological recording. Using this technique, it has been determined that the late phases of LTP maintenance are dependent on protein synthesis and there is some evidence that gene transcription is required. Although controversial, it has been proposed that LTP in the dentate gyrus and CA1 is expressed as an increase in affinity or number of postsynaptic AMPA receptors (Lynch and Baudry 1991). Others postulate that the expression is mediated by a persistent increase in the release of presynaptic glutamate, which is induced by a release of retrograde messengers from the postsynaptic neuron during LTP induction. In area CA1 and the dentate gyrus, the long-term expression of LTP is likely to be mediated by a combination of postsynaptic and presynaptic events, and a consequence of activation of various enzyme systems (Roberson, English, and Sweatt 1996; Abel et al. 1997). There is some evidence that LTP induces structural changes at the synapse (Buchs and Muller 1996), as well as induction of new sites of synaptic transmission (Bolshakov et al. 1997). Based on this cursory review, it should be clear that LTP is a complex phenomenon that involves the interaction of multiple cellular and molecular systems; the exact contribution of each has yet to be determined.
In addition to being a robust example of persistent changes in synaptic plasticity, LTP has been promoted as a putative neural mechanism of associative MEMORY formation or storage in the mammalian brain. It is generally believed that memory formation occurs through a strengthening of connections between neurons. In 1949, Donald HEBB wrote that, "When an axon of cell A ... excite(s) cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing B is increased" (p. 62). This supposition, known as Hebb's rule, is similar to the operational definition of LTP and is often cited as theoretical support for the putative role of LTP in learning and memory. In addition to theoretical support, the biological characteristics of LTP are in some respects similar to those of memory. First, LTP is prominent in the hippocampus, a structure considered necessary for aspects of declarative and spatial memory (Squire 1992). Second, LTP is long lasting, as is memory. Most forms of electrophysiological plasticity last milliseconds to seconds, while LTP persists from minutes to hours, even days (Staubli and Lynch 1987). In addition, LTP possesses physiological correlates of associativity and cooperativity, both properties of learning associated with classical CONDITIONING (Brown, Kairiss, and Keenan 1990). Finally, hippocampal LTP is optimally induced with a pattern of stimulation that mimics "theta," a naturally occurring brain rhythm (Larson and Lynch 1989). Theta rhythms are most often associated with motor activity and dreaming (Vanderwolf and Cain 1994), although they have been reported to occur in the hippocampus during learning (Otto et al. 1991) and stressful experience (Vanderwolf and Cain 1994; Shors and Matzel 1997).
Many behavioral studies addressing the role of LTP in memory take advantage of the fact that most types of LTP are dependent on NMDA receptor activation (Collingridge, Kehl, and McLennan 1983). When these receptors are blocked with competitive antagonists, rats are impaired in their ability to perform the Morris water maze, a spatial memory task that requires the hippocampus for acquisition. Recent evidence suggests that even during NMDA receptor blockade, rats can learn the location of new spatial cues if they were previously trained on a similar spatial task (Saucier and Cain 1995; Bannerman et al. 1995). Thus, NMDA receptor activation may not be necessary for learning about spatial cues per se, but may be involved in other aspects of performance necessary for successful completion of the task (Morris and Frey 1997; Shors and Matzel 1997). In addition to maze performance, NMDA receptor antagonists prevent fear conditioning (Kim et al. 1991), fear-potentiated startle (Campeau, Miserendino, and Davis 1992) and classic eyeblink conditioning (Servatius and Shors 1996). These tasks are not dependent on the hippocampus but rather are dependent on the AMYGDALA and CEREBELLUM, respectively. Thus, if LTP does play a role in memory, it may not be limited to hippocampal-dependent memories.
The relationship between LTP and learning has also been addressed using genetic techniques. Using a transgenic mouse in which a mutated and calcium-independent form of calmodulin (CaM) kinase II was expressed, researchers reported that LTP in response to theta-burst stimulation was reduced, as was the acquisition of spatial memories. In addition, the mutant mice possessed unstable and imprecise place cells in the hippocampus (Rotenberg et al. 1996). In another study, researchers expressed an inhibitory form of a protein kinase A regulatory subunit in mice and observed deficits in the late phase of LTP as well as deficits in hippocampal-dependent conditioning (Abel et al. 1997). Because the genes are altered throughout the life span, some deficits in plasticity and learning could be due to the abnormal developmental responses. Recently, transient knockouts have become available, providing more temporally and anatomically discrete lesions. Removal of a specific subunit of the NMDA receptor in the hippocampus after development disrupted LTP and spatial learning in the Morris water maze (Tsien, Huerta, and Tonegawa 1996).
A long-term increase in synaptic strength and efficacy is considered by many to be the best candidate to date for mediating the storage and retrieval of memories in the mammalian brain. This application of synaptic potentiation would constitute a memory system with massive storage capacity and fine resolution. Although appealing in principle, it remains to be determined whether increases in synaptic efficacy, such as LTP, are necessary for memory storage, whether they modify the rate and efficiency of memory formation (Shors and Matzel 1997), or do neither.
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Copyright © 1999 Massachusetts Institute of Technology