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Long-term potentiation
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Long-term potentiation

In neuroscience, long-term potentiation (LTP) refers to an extended period (minutes to hours in vitro and hours to days and months in vivo ) in which the connection between two nerve cells is strengthened or potentiated. The phenomenon was discovered in the mammalian hippocampus by Terje Lømo in 1966 and is popularly regarded as the cellular basis of memory.

Table of contents
1 Discovery and characterization
2 Properties of LTP
3 Models of LTP
4 Postsynaptic sufficiency and necessity
5 LTP and behavioral memory
6 Related topics
7 References

Discovery and characterization

LTP was first observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen. There, Lømo conducted a series of neurophysiological experiments exploring the role of the hippocampus in rat short-term memory. Targeting the synapses between granule cells of the perforant pathway and those of the dentate gyrus, Lømo elicited excitatory postsynaptic potentials (EPSPs) from dentate gyrus cells by stimulating the perforant pathway. He observed that a high-frequency train of stimulation produced larger, prolonged EPSPs compared to the responses evoked by a single stimulation. This phenomenon was soon dubbed "long-term potentiation".

Timothy Bliss, who joined the Andersen laboratory in 1969, collaborated with Lømo in 1973 to publish the first characterization of LTP in rabbit hippocampus.

Properties of LTP

LTP classically exhibits four main properties: rapid induction, cooperativity, associativity, and input specificity:

Models of LTP

One can imagine a finite number of ways in which the strength of a synapse might be enhanced. In brief, either 1) the presynaptic cell releases more neurotransmitter, 2) the postsynaptic cell's sensitivity to neurotransmitter is increased, or 3) both occur simultaneously.

Activity-dependent presynaptic facilitation

Until recent years, modern LTP research, driven by Nobel laureate Eric Kandel, focused on the presynaptic cell as the sole participant in the induction and maintenance of LTP [1]. Many such studies employed a simplified preparation of the marine snail Aplysia californica and analyzed the neurophysiology of its siphon-withdrawal reflex, finding that strong depolarization of presynaptic sensory neurons was sufficient for eliciting a prolonged and heightened postsynaptic response. Other studies of presynaptic cells revealed an increased number of neurotransmitter vesicles at facilitated synapses. Moreover, studies of the facilitatory role of the postsynaptic cell demonstrated that activation of the postsynaptic motor neuron was neither sufficient nor necessary for the induction of LTP [1]. Together, these studies gave rise to the popular notion that the presynaptic neuron was exclusively responsible for the facilitation of the postsynaptic response—a phenomenon known as activity-dependent presynaptic facilitation.

Hebbian LTP

In 1949, neuroscientist Donald Hebb introduced the Hebbian theory of synaptic plasticity, proposing that a synapse between two cells is only strengthened when both cells are active. With regard to long-term potentiation, Hebb's theory suggests that simultaneous activity of both pre- and postsynaptic cells is necessary for the induction of LTP. Indeed, modern work by David Glanzman [1] as well as Kandel [1] and many others support the role of a Hebbian process in the induction of LTP in Aplysia sensorimotor synapses. (See Postsynaptic sufficiency and necessity for an illustration of why previous work failed to recognize the role of the postsynaptic cell in LTP induction.)

In both vertebrates and invertebrates, such as Aplysia, this Hebbian LTP requires the elevation of postsynaptic Ca2+ and the activity of the NMDA receptor located on the postsynaptic cell. (This was demonstrated by applying either the Ca2+ chelator, BAPTA, or the NMDA receptor antagonist, APV, to the postsynaptic cell. Administering either subsequently prevents the induction of LTP.)

The initiation of Hebbian LTP is dependent on NMDA receptors, which are associative molecules able to detect simultaneous activity in the pre- and postsynaptic cell. Only when both neurons are active does the NMDA receptor allow Ca2+ to flow into the postsynaptic cell, initiating a cascade of events including postsynaptic modification (e.g., growth of new dendritic spines and insertion of new glutamate receptors into the postsynaptic membrane), activation of CREB, and the activation of the presynaptic cell via an unidentified retrograde messenger. This messenger serves to activate protein kinases (e.g., cAMP-dependent protein kinase) which would enhance presynaptic neurotransmitter release and thus further facilitate the postsynaptic response.

Postsynaptic sufficiency and necessity

In 1984, Carew et al demonstrated that postsynaptic activity was neither sufficient nor necessary for the induction of LTP [1]. Sufficiency experiments were carried out by stimulating the postsynaptic cell body with strong depolarizing current and then recording EPSPs that resulted from weak presynaptic stimulation. Researchers did not find the enhanced EPSPs previously observed with strong presynaptic depolarization alone, yielding the conclusion that postsynaptic activation was not sufficient to induce LTP.

In the necessity trials, a strong hyperpolarizing current was injected into the postsynaptic cell body while intense depolarizing current was applied to the presynaptic cell. The investigators' hypothesis was that if postsynaptic activity was required for the induction of LTP, then such strong hyperpolarizing current applied to the postsynaptic cell would prevent LTP induction. Indeed, researchers found instead that hyperpolarization of the postsynaptic cell did not prevent the induction of LTP, giving rise to the notion that postsynaptic activity was not necessary for LTP induction.

One source of error in the sufficiency and necessity experiments by Carew et al was that stimulation to the postsynaptic cell was consistently applied to the cell body rather than the postsynaptic density where synapses were made. Investigators thus made the incorrect assumption that the current applied to the soma would travel across neurites to the postsynaptic site without significant dissipation. However, the electrotonic distance between the soma and the postsynaptic density is quite large, resulting in significant dissipation of current by the time the postsynaptic site is reached. A reasonable explanation for the results of Carew et al is that the relevant synaptic sites on the postsynaptic cell were never depolarized during the sufficiency trials, and were never hyperpolarized in the necessity trials. Thus Carew et al received results in direct opposition to those of Lin and Glanzman, who successfully demonstrated that the postsynaptic cell was both sufficient and necessary for the induction of LTP [1].

LTP and behavioral memory

The mere fact that cultured synapses can undergo long-term potentiation when stimulated by electrodes says little about LTP's relation to memory. Several studies have provided some insight as to whether LTP is a requirement for memory.

NMDA blockade during spatial learning

Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories [1]. He tested the spatial memory of two groups of rats, one whose hippocampi were bathed in the NMDA receptor blocker APV, and the other acting as a control group. (The hippocampus, where LTP was originally observed, is required for spatial learning.) Both groups were then subjected to the Morris water maze, in which rats were placed into a pool of murky water and tested on how quickly they could locate a platform hidden beneath the water surface.

Rats in the control group were able to locate the platform and escape from the pool, whereas the ability of APV-treated rats to complete the task was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups of rats, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided some evidence that the NMDA receptor — and thus LTP — was somehow involved with at least some types of learning and memory.

Similarly, Susumo Tonegawa has demonstrated that a specific region of the hippocampus, namely CA1, is crucial to the formation of spatial memories [1]. So-called place cells located in this region are responsible for creating "place fields" of the rat's environment, which may be roughly equated with maps of the rat's surroundings. The accuracy of these maps determines how well a rat learns about its environment, and thus how well it can navigate about it.

Tonegawa found that by impairing the NMDA receptor, specifically by genetically removing the NMDAR1 subunit in the CA1 region, the place fields generated were substantially less specific than those of controls. That is, rats produced faulty spatial maps when their NMDA receptors were impaired. As expected, these rats performed very poorly on spatial tasks compared to controls, providing more support to the notion that LTP is the underlying mechanism of spatial learning.

"Doogie mice"

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. Joe Tsein produced a line of mice with enhanced NMDA receptor function by overexpressing the NR2B subunit in the hippocampus [1]. These mice, nicknamed "Doogie mice" after the precocious doctor Doogie Howser, had larger long-term potentiation and excelled at spatial learning tasks, once again suggesting LTP's involvement in the formation of hippocampal-dependent memories.

Related topics

References