In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.
It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength. As memories are thought to be encoded by modification of synaptic strength, LTP is widely considered one of the major cellular mechanisms that underlies learning and memory.
LTP was discovered in the rabbit hippocampus by Terje Lømo in 1966 and has remained a popular subject of research since. Many modern LTP studies seek to better understand its basic biology, while others aim to draw a causal link between LTP and behavioral learning. Still, others try to develop methods, pharmacologic or otherwise, of enhancing LTP to improve learning and memory. LTP is also a subject of clinical research, for example, in the areas of Alzheimer's disease and addiction medicine.
History
Early theories of learning
At the end of the 19th century, scientists generally recognized that the number of neurons in the adult brain (roughly 100 billion) did not increase significantly with age, giving neurobiologists good reason to believe that memories were generally not the result of new neuron production. With this realization came the need to explain how memories could form in the absence of new neurons.
The Spanish neuroanatomist Santiago Ramón y Cajal was among the first to suggest a mechanism of learning that did not require the formation of new neurons. In his 1894 Croonian Lecture, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. Hebbian theory, introduced by Donald Hebb in 1949, echoed Ramón y Cajal's ideas, further proposing that cells may grow new connections or undergo metabolic and synaptic changes that enhance their ability to communicate and create a neural network of experiences:
Eric Kandel (1964) and associates were some of the first researchers to discover long-term potentiation during their work with sea slug Aplysia. They attempted to apply behavioral conditioning to different cells in the slug's neural network. Their results showed synaptic strength changes and researchers suggested that this may be due to a basic form of learning occurring within the slug.
Though these theories of memory formation are now well established, they were farsighted for their time: late 19th and early 20th century neuroscientists and psychologists were not equipped with the neurophysiological techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the later half of the 20th century, at about the same time as the discovery of long-term potentiation.
Discovery
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 on anesthetized rabbits to explore the role of the hippocampus in short-term memory.
Lømo's experiments focused on connections, or synapses, from the perforant pathway to the dentate gyrus. These experiments were carried out by stimulating presynaptic fibers of the perforant pathway and recording responses from a collection of postsynaptic cells of the dentate gyrus. As expected, a single pulse of electrical stimulation to fibers of the perforant pathway caused excitatory postsynaptic potentials (EPSPs) in cells of the dentate gyrus. What Lømo unexpectedly observed was that the postsynaptic cells' response to these single-pulse stimuli could be enhanced for a long period of time if he first delivered a high-frequency train of stimuli to the presynaptic fibers. When such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell population. This phenomenon, whereby a high-frequency stimulus could produce a long-lived enhancement in the postsynaptic cells' response to subsequent single-pulse stimuli, was initially called "long-lasting potentiation".
Timothy Bliss, who joined the Andersen laboratory in 1968, collaborated with Lømo and in 1973 the two published the first characterization of long-lasting potentiation in the rabbit hippocampus. Bliss and Tony Gardner-Medwin published a similar report of long-lasting potentiation in the awake animal which appeared in the same issue as the Bliss and Lømo report. In 1975, Douglas and Goddard proposed "long-term potentiation" as a new name for the phenomenon of long-lasting potentiation.While the term "long term potentiation" appeared once in the original Bliss and Lømo paper, it was not formally proposed for the phenomenon until the Douglas and Goddard paper. Andersen suggested that the authors chose "long-term potentiation" perhaps because of its easily pronounced acronym, "LTP".
Models and theory
The physical and biological mechanism of LTP is still not understood, but some successful models have been developed. Studies of dendritic spines, protruding structures on dendrites that physically grow and retract over the course of minutes or hours, have suggested a relationship between the electrical resistance of the spine and the effective synapse strength, due to their relationship with intracellular calcium transients. Mathematical models such as BCM Theory, which depends also on intracellular calcium in relation to NMDA receptor voltage gates, have been developed since the 1980s and modify the traditional a priori Hebbian learning model with both biological and experimental justification. Still, others have proposed re-arranging or synchronizing the relationship between receptor regulation, LTP, and synaptic strength.
Types Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the cerebral cortex, cerebellum, amygdala, and many others. Robert Malenka, a prominent LTP researcher, has suggested that LTP may even occur at all excitatory synapses in the mammalian brain.
Different areas of the brain exhibit different forms of LTP. The specific type of LTP exhibited between neurons depends on a number of factors. One such factor is the age of the organism when LTP is observed. For example, the molecular mechanisms of LTP in the immature hippocampus differ from those mechanisms that underlie LTP of the adult hippocampus. The signalling pathways used by a particular cell also contribute to the specific type of LTP present. For example, some types of hippocampal LTP depend on the NMDA receptor, others may depend upon the metabotropic glutamate receptor (mGluR), while still others depend upon another molecule altogether. The variety of signaling pathways that contribute to LTP and the wide distribution of these various pathways in the brain are reasons that the type of LTP exhibited between neurons depends only in part upon the anatomic location in which LTP is observed. For example, LTP in the Schaffer collateral pathway of the hippocampus is NMDA receptor-dependent - this was proved by the application of AP5, an antagonist to the NMDA receptor, which prevented LTP in this pathway. Conversely, LTP in the mossy fiber pathway is NMDA receptor-independent, even though both pathways are in the hippocampus.
The pre- and postsynaptic activity required to induce LTP are other criteria by which LTP is classified. Broadly, this allows classification of LTP into Hebbian, non-Hebbian, and anti-Hebbian mechanisms. Borrowing its name from Hebb's postulate, summarized by the maxim that "cells that fire together wire together," Hebbian LTP requires simultaneous pre- and postsynaptic depolarization for its induction. Non-Hebbian LTP is a type of LTP that does not require such simultaneous depolarization of pre- and postsynaptic cells; an example of this occurs in the mossy fiber hippocampal pathway. A special case of non-Hebbian LTP, anti-Hebbian LTP explicitly requires simultaneous presynaptic depolarization and relative postsynaptic hyperpolarization for its induction.
Owing to its predictable organization and readily inducible LTP, the CA1 hippocampus has become the prototypical site of mammalian LTP study. In particular, NMDA receptor-dependent LTP in the adult CA1 hippocampus is the most widely studied type of LTP, and is therefore, the focus of this article.
Properties NMDA receptor-dependent LTP exhibits several properties, including input specificity, associativity, cooperativity, and persistence.
Input specificity Once induced, LTP at one synapse does not spread to other synapses; rather LTP is input specific. Long-term potentiation is only propagated to those synapses according to the rules of associativity and cooperativity. However, the input specificity of LTP may be incomplete at short distances. One model to explain the input specificity of LTP was presented by Frey and Morris in 1997 and is called the synaptic tagging and capture hypothesis.
Associativity Associativity refers to the observation that when weak stimulation of a single pathway is insufficient for the induction of LTP, simultaneous strong stimulation of another pathway will induce LTP at both pathways.
Cooperativity LTP can be induced either by strong tetanic stimulation of a single pathway to a synapse, or cooperatively via the weaker stimulation of many. When one pathway into a synapse is stimulated weakly, it produces insufficient postsynaptic depolarization to induce LTP. In contrast, when weak stimuli are applied to many pathways that converge on a single patch of postsynaptic membrane, the individual postsynaptic depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP cooperatively. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and cooperativity. Bruce McNaughton argues that any difference between associativity and cooperativity is strictly semantic. Experiments performed by stimulating an array of individual dendritic spines, have shown that synaptic cooperativity by as few as two adjacent dendritic spines prevents long term depression (LTD) allowing only LTP.
Persistence LTP is persistent, lasting from several minutes to many months, and it is this persistence that separates LTP from other forms of synaptic plasticity.
Early phase
Maintenance While induction entails the transient activation of CaMKII and PKC, maintenance of E-LTP (early-form LTP) is characterized by their persistent activation. During this stage PKMzeta (PKMζ) which does not have dependence on calcium, become autonomously active. Consequently, they are able to carry out the phosphorylation events that underlie E-LTP expression.
Expression