Long-term potentiation
Overview
 
In neuroscience
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...

, long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

, the ability of chemical synapse
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...

s 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
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...

 and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....

.

LTP shares many features with long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

, making it an attractive candidate for a cellular mechanism of learning.
Encyclopedia
In neuroscience
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...

, long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

, the ability of chemical synapse
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...

s 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
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...

 and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....

.

LTP shares many features with long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

, making it an attractive candidate for a cellular mechanism of learning. For example, LTP and long-term memory are triggered rapidly, each depends upon the synthesis of new proteins
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

, each has properties of associativity, and each can last for many months. LTP may account for many types of learning, from the relatively simple classical conditioning
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...

 present in all animals, to the more complex, higher-level cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...

 observed in humans.

At a cellular level, LTP enhances synaptic transmission. It improves the ability of two neurons, one presynaptic and the other postsynaptic, to communicate with one another across a synapse. The precise molecular mechanisms for this enhancement of transmission have not been fully established, in part because LTP is governed by multiple mechanisms that vary by species and brain region. In the most well understood form of LTP, enhanced communication is predominantly carried out by improving the postsynaptic cell's sensitivity to signals received from the presynaptic cell. These signals, in the form of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

 molecules, are received by neurotransmitter receptor
Neurotransmitter receptor
A Neurotransmitter receptor is a membrane receptor protein that is activated by a Neurotransmitter. A membrane protein interacts with the lipid bilayer that encloses the cell and a membrane receptor protein interacts with a chemical in the cells external environment, which binds to the cell...

s present on the surface of the postsynaptic cell. LTP improves the postsynaptic cell's sensitivity to neurotransmitter in large part by increasing the activity of existing receptors and by increasing the number of receptors on the postsynaptic cell surface.

LTP was discovered in the rabbit hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

 by Terje Lømo
Per Andersen
Per Oskar Andersen is a Norwegian brain researcher at the University of Oslo. Research by his lab, specifically by Terje Lømo , led to the discovery of long-term potentiation in 1966.He is a member of the Norwegian Academy of Science and Letters.He is also a fellow at the Royal...

 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
Clinical research
Clinical research is a branch of medical science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use...

, for example, in the areas of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 and addiction medicine
Addiction Medicine
Addiction medicine is a medical specialty that deals with the treatment of addiction. The specialty often crosses over into other areas, since various aspects of addiction fall within the fields of public health, psychology, social work, psychiatry, and internal medicine, among others...

.

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
Spain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...

 neuroanatomist Santiago Ramón y Cajal
Santiago Ramón y Cajal
Santiago Ramón y Cajal ForMemRS was a Spanish pathologist, histologist, neuroscientist, and Nobel laureate. His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience...

 was among the first to suggest a mechanism of learning that did not require the formation of new neurons. In his 1894 Croonian Lecture
Croonian Lecture
The Croonian Lectures are prestigious lectureships given at the invitation of the Royal Society and the Royal College of Physicians.Among the papers of William Croone at his death in 1684, was a plan to endow one lectureship at both the Royal Society and the Royal College of Physicians...

, he proposed that memories might instead be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. Hebbian theory
Hebbian theory
Hebbian theory describes a basic mechanism for synaptic plasticity wherein an increase in synaptic efficacy arises from the presynaptic cell's repeated and persistent stimulation of the postsynaptic cell...

, introduced by Donald Hebb
Donald Olding Hebb
Donald Olding Hebb FRS was a Canadian psychologist who was influential in the area of neuropsychology, where he sought to understand how the function of neurons contributed to psychological processes such as learning...

 in 1949, echoed Ramón y Cajal's ideas, further proposing that cells may grow new connections or undergo metabolic changes that enhance their ability to communicate:
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
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...

 techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the latter 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
Oslo
Oslo is a municipality, as well as the capital and most populous city in Norway. As a municipality , it was established on 1 January 1838. Founded around 1048 by King Harald III of Norway, the city was largely destroyed by fire in 1624. The city was moved under the reign of Denmark–Norway's King...

, Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...

, laboratory of Per Andersen
Per Andersen
Per Oskar Andersen is a Norwegian brain researcher at the University of Oslo. Research by his lab, specifically by Terje Lømo , led to the discovery of long-term potentiation in 1966.He is a member of the Norwegian Academy of Science and Letters.He is also a fellow at the Royal...

. There, Lømo conducted a series of neurophysiological
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...

 experiments on anesthetized
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

 rabbits to explore the role of the hippocampus in short-term memory
Short-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...

.

Lømo's experiments focused on connections, or synapses, from the perforant pathway to the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...

. 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 potential
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...

s (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
Tetanic stimulation
In neurobiology, a tetanic stimulation consists of a high-frequency sequence of individual stimulations of a neuron. It is associated with long-term potentiation....

 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
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...

 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. 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.http://www.scholarpedia.org/article/Models_of_synaptic_plasticity 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
Electrical resistance
The electrical resistance of an electrical element is the opposition to the passage of an electric current through that element; the inverse quantity is electrical conductance, the ease at which an electric current passes. Electrical resistance shares some conceptual parallels with the mechanical...

 of the spine and the effective synapse strength, due to their relationship with intracellular calcium transients. Mathematical models such as BCM Theory
BCM theory
BCM theory, BCM synaptic modification, or the BCM rule, named for Elie Bienenstock, Leon Cooper, and Paul Munro, is a physical theory of learning in the visual cortex developed in 1981...

, which depends also on intracellular calcium in relation to NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

 voltage gates
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....

, 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
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

, amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...

, 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
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

, others may depend upon the metabotropic glutamate receptor
Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...

 (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 in part upon the anatomic location in which LTP is observed. For example, LTP in the Schaffer collateral
Schaffer collateral
Schaffer collaterals are axon collaterals given off by CA3 pyramidal cells in the hippocampus. These collaterals project to area CA1 of the hippocampus and are an integral part of memory formation and the emotional network of the Papez circuit, and of the hippocampal trisynaptic loop...

 pathway of the hippocampus is NMDA receptor-dependent, whereas LTP in the mossy fiber
Mossy fiber (hippocampus)
In the hippocampus, granule cells of the dentate gyrus form distinctive unmyelinated axons that project along the mossy fiber pathway to the CA3 region. The axons emerge from the basal portions of the granule cells and pass through the hilus of the dentate gyrus before entering the stratum...

 pathway is NMDA receptor-independent.

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
Synaptic tagging
Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Frey and Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product trafficking essential for sustained LTP and LTD...

 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
Tetany (action potential summation)
Tetany is a case of involuntary muscle convulsion. It is a muscular physical state at which action potentials from nerves arrive to the skeletal muscle motor end plate rapidly enough in succession to cause a steady contraction. This differs from individual twitches in that the twitches are summed...

 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.


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
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

.

Mechanism

Long-term potentiation occurs through a variety of mechanisms throughout the nervous system; no single mechanism unites all of LTP's many types. However, for the purposes of study, LTP is commonly divided into three phases that occur sequentially: short-term potentiation, early LTP, and late LTP. Little is known about the mechanisms of short-term potentiation, so it will not be discussed here.

Each phase of LTP is governed by a set of mediators, small molecules that dictate the events of that phase. These molecules include protein receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 that respond to events outside of the cell, enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s that carry out chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

s within the cell, and signaling molecule
Signaling molecule
A signaling molecule is a chemical involved in transmitting information between cells. Such molecules are released from the cell sending the signal, cross over the gap between cells by diffusion, and interact with specific receptors in another cell, triggering a response in that cell by activating...

s that allow the progression from one phase to the next. In addition to these mediators, there are also modulator molecules, described later, that interact with mediators to finely alter the LTP ultimately generated.

The early (E-LTP) and late (L-LTP) phases of LTP are each characterized by a series of three events: induction, maintenance, and expression. Induction is the process by which a short-lived signal triggers that phase of LTP to begin. Maintenance corresponds to the persistent biochemical changes that occur in response to the induction of that phase. Expression entails the long-lasting cellular changes that result from activation of the maintenance signal. Thus the mechanisms of LTP can be discussed in terms of the mediators that underlie the induction, maintenance, and expression of E-LTP and L-LTP.

Early phase

Induction

Induction of E-LTP occurs when the concentration of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 inside the postsynaptic cell exceeds a critical threshold. In many types of LTP, the flow of calcium into the cell requires the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

, which is why these types of LTP are considered to be NMDA receptor-dependent. NMDA receptor-dependent LTP can be induced experimentally by applying a few trains of high-frequency stimuli to the connection between two neurons. An understanding of normal synaptic transmission illustrates how this tetanic
Tetany (action potential summation)
Tetany is a case of involuntary muscle convulsion. It is a muscular physical state at which action potentials from nerves arrive to the skeletal muscle motor end plate rapidly enough in succession to cause a steady contraction. This differs from individual twitches in that the twitches are summed...

 stimulation can induce E-LTP.

Chemical synapse
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...

s are functional connections between neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s throughout the nervous system. In a typical synapse, information is passed from the first (presynaptic) neuron to the second (postsynaptic) neuron via a process of synaptic transmission. Through experimental manipulation, a non-tetanic stimulus can be applied to the presynaptic cell, causing it to release a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

—typically glutamate—onto the postsynaptic cell membrane. There, glutamate binds to AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...

s (AMPARs) embedded in the postsynaptic membrane. The AMPA receptor is one of the main excitatory receptors in the brain, and is responsible for most of its rapid, moment-to-moment excitatory activity. Glutamate binding to the AMPA receptor triggers the influx of positively charged sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 ions into the postsynaptic cell, causing a short-lived depolarization called the excitatory postsynaptic potential
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...

 (EPSP).

The magnitude of this depolarization determines whether E-LTP will be induced in the postsynaptic cell. While a single stimulus does not generate an EPSP capable of inducing E-LTP, repeated stimuli given at high frequency cause the postsynaptic cell to be progressively depolarized as a result of EPSP summation: with each EPSP reaching the postsynaptic cell before the previous EPSP can decay, successive EPSPs add to the depolarization caused by the previous EPSPs. In synapses that exhibit NMDA receptor-dependent LTP, sufficient depolarization unblocks NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

s (NMDARs), receptors that allow calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 to flow into the cell when bound by glutamate. While NMDARs are present at most postsynaptic membranes, at resting membrane potentials they are blocked by a magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...

 ion that prevents the entry of calcium into the postsynaptic cell. Sufficient depolarization through the summation of EPSPs relieves the magnesium blockade of the NMDAR, allowing calcium influx (despite the reduced driving force for calcium entry). The rapid rise in intracellular calcium concentration triggers the short-lasting activation of several enzymes that mediate E-LTP induction. Of particular importance are some protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...

 enzymes, including calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...

 (PKC). To a lesser extent, protein kinase A (PKA) and mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...

 (MAPK) activation also contribute to the induction of E-LTP.

Maintenance

While induction entails the transient activation of CaMKII and PKC, maintenance of E-LTP is characterized by their persistent activation. During this stage, PKMz(Protein kinase Mζ) 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

Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 is a chemical reaction in which a small phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 group is added to another molecule to change that molecule's activity. Autonomously active CaMKII and PKC use phosphorylation to carry out the two major mechanisms underlying the expression of E-LTP. First, and most importantly, they phosphorylate existing AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...

s to increase their activity. Second, they mediate or modulate the insertion of additional AMPA receptors into the postsynaptic membrane. Importantly, the delivery of AMPA receptors to the synapse during E-LTP is independent of protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

. This is achieved by having a nonsynaptic pool of AMPA receptors adjacent to the postsynaptic membrane. When the appropriate LTP-inducing stimulus arrives, nonsynaptic AMPA receptors are rapidly trafficked into the postsynaptic membrane under the influence of protein kinases. As mentioned previously, AMPA receptors are the brain's most abundant glutamate receptors and mediate the majority of its excitatory activity. By increasing the efficiency and number of AMPA receptors at the synapse, future excitatory stimuli generate larger postsynaptic responses.

While the above model of E-LTP describes entirely postsynaptic mechanisms for induction, maintenance, and expression, an additional component of expression may occur presynaptically. One hypothesis of this presynaptic facilitation is that persistent CaMKII activity during E-LTP may lead to the synthesis of a "retrograde messenger", discussed later. According to this hypothesis, the newly synthesized messenger travels across the synaptic cleft from the postsynaptic to the presynaptic cell, leading to a chain of events that facilitate the presynaptic response to subsequent stimuli. Such events may include an increase in neurotransmitter vesicle number, probability of vesicle release, or both. In addition to the retrograde messenger underlying presynaptic expression in early LTP, the retrograde messenger may also play a role in the expression of late LTP.

Late phase

Late LTP is the natural extension of E-LTP. Unlike E-LTP, which is independent of protein synthesis, L-LTP requires gene transcription and protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

 in the postsynaptic cell. Two phases of L-LTP exist: the first depends upon protein synthesis, while the second depends upon both gene transcription and protein synthesis. These phases are occasionally called LTP2 and LTP3, respectively, with E-LTP referred to as LTP1 under this nomenclature.

Induction

Late LTP is induced by changes in gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

 and protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...

 brought about by the persistent activation of protein kinases activated during E-LTP, such as MAPK. In fact, MAPK—specifically the extracellular signal-regulated kinase (ERK) subfamily of MAPKs—may be the molecular link between E-LTP and L-LTP, since many signaling cascades involved in E-LTP, including CaMKII and PKC, can converge on ERK. Recent research has shown that the induction of L-LTP can depend on coincident molecular events, namely PKA activation and calcium influx, that converge on CRTC1 (TORC1), a potent transcriptional coactivator for cAMP response element binding protein (CREB). This requirement for a molecular coincidence accounts perfectly for the associative nature of LTP, and, presumably, for that of learning.

Maintenance

Upon activation, ERK may phosphorylate a number of cytoplasmic and nuclear molecules that ultimately result in the protein synthesis and morphological changes observed in L-LTP. These cytoplasmic and nuclear molecules may include transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s such as CREB. ERK-mediated changes in transcription factor activity may trigger the synthesis of proteins that underlie the maintenance of L-LTP. One such molecule may be protein kinase Mζ (PKMζ), a persistently active kinase whose synthesis increases following LTP induction. PKMζ is an atypical isoform of PKC that lacks a regulatory subunit and thus remains constitutively active. Unlike other kinases that mediate LTP, PKMζ is active not just in the first 30 minutes following LTP induction; rather, PKMζ becomes a requirement for LTP maintenance only during the late phase of LTP. PKMζ thus appears important for the persistence of memory and would be expected to be important in the maintenance of long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

. Indeed, administration of a PKMζ inhibitor into the hippocampi of rats results in retrograde amnesia
Retrograde amnesia
Retrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....

 with intact short-term memory
Short-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...

; PKMζ does not play a role in the establishment of short-term memory. PKMζ has recently been shown to underlie L-LTP maintenance by directing the trafficking and reorganization of proteins in the synaptic scaffolding that underlie the expression of L-LTP.

Expression

Aside from PKMζ, the identities of only a few proteins synthesized during L-LTP are known. Regardless of their identities, it is thought that they contribute to the increase in dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...

 number, surface area, and postsynaptic sensitivity to neurotransmitter associated with L-LTP expression. The latter may be brought about in part by the enhanced synthesis of AMPA receptors during L-LTP. Late LTP is also associated with the presynaptic synthesis of synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...

 and an increase in synaptic vesicle
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...

 number, suggesting that L-LTP induces protein synthesis not only in postsynaptic cells, but in presynaptic cells as well. As mentioned previously, for postsynaptic LTP induction to result in presynaptic protein synthesis, there must be communication from the postsynaptic to the presynaptic cell. This may occur via the synthesis of a retrograde messenger, discussed later.

Even in studies restricted to postsynaptic events, investigators have not determined the location of the protein synthesis that underlies L-LTP. Specifically, it is unclear whether protein synthesis takes place in the postsynaptic cell body or in its dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...

s. Despite having observed ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s (the major components of the protein synthesis machinery) in dendrites as early as the 1960s, prevailing wisdom was that the cell body was the predominant site of protein synthesis in neurons. This reasoning was not seriously challenged until the 1980s, when investigators reported observing protein synthesis in dendrites whose connection to their cell body had been severed. More recently, investigators have demonstrated that this type of local protein synthesis is necessary for some types of LTP.

One reason for the popularity of the local protein synthesis hypothesis is that it provides a possible mechanism for the specificity associated with LTP. Specifically, if indeed local protein synthesis underlies L-LTP, only dendritic spines receiving LTP-inducing stimuli will undergo LTP; the potentiation will not be propagated to adjacent synapses. By contrast, global protein synthesis that occurs in the cell body requires that proteins be shipped out to every area of the cell, including synapses that have not received LTP-inducing stimuli. Whereas local protein synthesis provides a mechanism for specificity, global protein synthesis would seem to directly compromise it. However, as discussed later, the synaptic tagging hypothesis successfully reconciles global protein synthesis, synapse specificity, and associativity.

Retrograde signaling

Retrograde signaling is a hypothesis that attempts to explain that, while LTP is induced and expressed postsynaptically, some evidence suggests that it is expressed presynaptically as well. The hypothesis gets its name because normal synaptic transmission is directional and proceeds from the presynaptic to the postsynaptic cell. For induction to occur postsynaptically and be partially expressed presynaptically, a message must travel from the postsynaptic cell to the presynaptic cell in a retrograde (reverse) direction. Once there, the message presumably initiates a cascade of events that leads to a presynaptic component of expression, such as the increased probability of neurotransmitter vesicle release.

Retrograde signaling is currently a contentious subject as some investigators do not believe the presynaptic cell contributes at all to the expression of LTP. Even among proponents of the hypothesis there is controversy over the identity of the messenger. Early thoughts focused on nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

, while most recent evidence points to cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...

 proteins.

Synaptic tagging

Before the local protein synthesis hypothesis gained significant support, there was general agreement that the protein synthesis underlying L-LTP occurred in the cell body. Further, there was thought that the products of this synthesis were shipped cell-wide in a nonspecific manner. It thus became necessary to explain how protein synthesis could occur in the cell body without compromising LTP's input specificity. The synaptic tagging hypothesis attempts to solve the cell's difficult problem of synthesizing proteins in the cell body but ensuring they only reach synapses that have received LTP-inducing stimuli.

The synaptic tagging hypothesis proposes that a "synaptic tag" is synthesized at synapses that have received LTP-inducing stimuli, and that this synaptic tag may serve to capture plasticity-related proteins shipped cell-wide from the cell body. Studies of LTP in the marine snail
Nudibranch
A nudibranch is a member of what is now a taxonomic clade, and what was previously a suborder, of soft-bodied, marine gastropod mollusks which shed their shell after their larval stage. They are noted for their often extraordinary colors and striking forms...

 Aplysia californica have implicated synaptic tagging as a mechanism for the input-specificity of LTP. There is some evidence that given two widely separated synapses, an LTP-inducing stimulus at one synapse drives several signaling cascades (described previously) that initiates gene expression in the cell nucleus. At the same synapse (but not the unstimulated synapse), local protein synthesis creates a short-lived (less than three hours) synaptic tag. The products of gene expression are shipped globally throughout the cell, but are only captured by synapses that express the synaptic tag. Thus only the synapse receiving LTP-inducing stimuli is potentiated, demonstrating LTP's input specificity.

The synaptic tag hypothesis may also account for LTP's associativity and cooperativity. Associativity (see Properties) is observed when one synapse is excited with LTP-inducing stimulation while a separate synapse is only weakly stimulated. Whereas one might expect only the strongly stimulated synapse to undergo LTP (since weak stimulation alone is insufficient to induce LTP at either synapse), both synapses will in fact undergo LTP. While weak stimuli are unable to induce protein synthesis in the cell body, they may prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, capable of inducing cell body protein synthesis, then may prompt the production of plasticity-related proteins, which are shipped cell-wide. With both synapses expressing the synaptic tag, both would capture the protein products resulting in the expression of LTP in both the strongly stimulated and weakly stimulated pathways.

Cooperativity is observed when two synapses are activated by weak stimuli incapable of inducing LTP when stimulated individually. But upon simultaneous weak stimulation, both synapses undergo LTP in a cooperative fashion. Synaptic tagging does not explain how multiple weak stimuli can result in a collective stimulus sufficient to induce LTP (this is explained by the postsynaptic summation of EPSPs described previously). Rather, synaptic tagging explains the ability of weakly stimulated synapses, none of which are capable of independently generating LTP, to receive the products of protein synthesis initiated collectively. As before, this may be accomplished through the synthesis of a local synaptic tag following weak synaptic stimulation.

Modulation

Proposed modulators of LTP
Modulator Target
β-Adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....

 
cAMP, MAPK amplification
Nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

 
Guanylyl cyclase, PKG, NMDAR
Dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....

 
cAMP, MAPK amplification
Metabotropic glutamate receptor
Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...

 
PKC, MAPK amplification


As described previously, the molecules that underlie LTP can be classified as mediators or modulators. A mediator of LTP is a molecule, such as the NMDA receptor or calcium, whose presence and activity is necessary for generating LTP under nearly all conditions. By contrast, a modulator is a molecule that can alter LTP but is not essential for its generation or expression.

In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the steroid hormone
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...

 estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...

 may enhance LTP by driving CREB phosphorylation and subsequent dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...

 growth. Additionally, β-adrenergic receptor agonists such as norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 may alter the protein synthesis-dependent late phase of LTP. Nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

 activity may also result in the subsequent activation of guanylyl cyclase and PKG. Similarly, activation of dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....

s may enhance LTP through the cAMP/PKA signaling pathway.

Relationship to behavioral memory

While the long-term potentiation of synapses in cell culture seems to provide an elegant substrate for learning and memory, the contribution of LTP to behavioral learning — that is, learning at the level of the whole organism — cannot simply be extrapolated from in vitro studies. For this reason, considerable effort has been dedicated to establishing whether LTP is a requirement for learning and memory in living animals.

Spatial memory

In 1986, Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories in vivo. He tested the spatial memory
Spatial memory
In cognitive psychology and neuroscience, spatial memory is the part of memory responsible for recording information about one's environment and its spatial orientation. For example, a person's spatial memory is required in order to navigate around a familiar city, just as a rat's spatial memory is...

 of rats by pharmacologically modifying their hippocampus, a brain structure whose role in spatial learning is well established. Rats were trained on the Morris water maze
Morris water maze
The Morris water navigation task is a behavioral procedure widely used in behavioral neuroscience to study spatial learning and memory. It was developed by neuroscientist Richard G...

, a spatial memory task in which rats swim in a pool of murky water until they locate the platform hidden beneath its surface. During this exercise, normal rats are expected to associate the location of the hidden platform with salient cues placed at specific positions around the circumference of the maze. After training, one group of rats had their hippocampi bathed in the NMDA receptor blocker APV
APV (NMDAR antagonist)
AP5 or APV is a selective NMDA receptor antagonist that competitively inhibits the ligand binding site of NMDA receptors....

, while the other group served as the control. Both groups were then subjected to the water maze spatial memory task. Rats in the control group were able to locate the platform and escape from the pool, while the performance of APV-treated rats was significantly impaired. Moreover, when slices of the hippocampus were taken from both groups, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided early evidence that the NMDA receptor — and by extension, LTP — was required for at least some types of learning and memory.

Similarly, Susumu Tonegawa
Susumu Tonegawa
Susumu Tonegawa is a Japanese scientist who won the Nobel Prize for Physiology or Medicine in 1987 for his discovery of the genetic mechanism that produces antibody diversity. Although he won the Nobel Prize for his work in immunology, Tonegawa is a molecular biologist by training...

 demonstrated in 1996 that the CA1 area of the hippocampus is crucial to the formation of spatial memories in living mice. So-called place cell
Place cell
Place cells are neurons in the hippocampus that exhibit a high rate of firing whenever an animal is in a specific location in an environment corresponding to the cell's "place field". These neurons are distinct from other neurons with spatial firing properties, such as grid cells, border cells,...

s
located in this region become active only when the rat is in a particular location — called a place field — in the environment. Since these place fields are distributed throughout the environment, one interpretation is that groups of place cells form maps in the hippocampus. The accuracy of these maps determines how well a rat learns about its environment and thus how well it can navigate it. Tonegawa found that by impairing the NMDA receptor, specifically by genetically removing the NR1 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, further supporting the role of LTP in spatial learning.

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. In 1999, Tang et al. produced a line of mice with enhanced NMDA receptor function by overexpressing the NR2B subunit in the hippocampus. The resulting smart mice, nicknamed "Doogie mice" after the fictional prodigious doctor Doogie Howser, had larger LTP and excelled at spatial learning tasks, reinforcing LTP's importance in the formation of hippocampus-dependent memories.

Inhibitory avoidance

In 2006, Jonathan Whitlock and colleagues reported on a series of experiments that provided perhaps the strongest evidence of LTP's role in behavioral memory, arguing that to conclude that LTP underlies behavioral learning, the two processes must both mimic and occlude one another. Employing an inhibitory avoidance learning paradigm, researchers trained rats in a two-chambered apparatus with light and dark chambers, the latter being fitted with a device that delivered a foot shock to the rat upon entry. An analysis of CA1 hippocampal synapses revealed that inhibitory avoidance training induced in vivo AMPA receptor phosphorylation of the same type as that seen in LTP in vitro; that is, inhibitory avoidance training mimicked LTP. In addition, synapses potentiated during training could not be further potentiated by experimental manipulations that would have otherwise induced LTP; that is, inhibitory avoidance training occluded LTP. In a response to the article, Timothy Bliss and colleagues remarked that these and related experiments "substantially advance the case for LTP as a neural mechanism for memory."

Clinical significance

The role of LTP in disease is less clear than its role in basic mechanisms of synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

. However, alterations in LTP may contribute to a number of neurological diseases, including depression, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

, and neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...

. Impaired LTP may also have a role in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 and drug addiction.

Alzheimer's disease

LTP has received much attention among those who study Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 (AD), a neurodegenerative disease that causes marked cognitive decline and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

. Much of this deterioration occurs in association with degenerative changes in the hippocampus and other medial temporal lobe structures. Because of the hippocampus' well established role in LTP, some have suggested that the cognitive decline seen in individuals with AD may result from impaired LTP.

In a 2003 review of the literature, Rowan et al. proposed one model for how LTP might be affected in AD. AD appears to result, at least in part, from misprocessing of amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 (APP). The result of this abnormal processing is the accumulation of fragments of this protein, called amyloid β (Aβ). Aβ exists in both soluble and fibrillar forms. Misprocessing of APP results in the accumulation of soluble Aβ that, according to Rowan's hypothesis, impairs hippocampal LTP and may lead to the cognitive decline seen early in AD.

AD may also impair LTP through mechanisms distinct from Aβ. For example, one study demonstrated that the enzyme PKMζ accumulates in neurofibrillary tangle
Neurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...

s, which are a pathologic marker of AD. PKMζ is an enzyme with critical importance in the maintenance of late LTP.

Drug addiction

Research in the field of addiction medicine
Addiction Medicine
Addiction medicine is a medical specialty that deals with the treatment of addiction. The specialty often crosses over into other areas, since various aspects of addiction fall within the fields of public health, psychology, social work, psychiatry, and internal medicine, among others...

 has also recently turned its focus to LTP, owing to the hypothesis that drug addiction represents a powerful form of learning and memory. Addiction is a complex neurobehavioral phenomenon involving various parts of the brain, such as the ventral tegmental area (VTA) and nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...

 (NAc). Studies have demonstrated that VTA and NAc synapses are capable of undergoing LTP and that this LTP may be responsible for the behaviors that characterize addiction.

See also

  • Synaptic plasticity
    Synaptic plasticity
    In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

  • Neuroplasticity
    Neuroplasticity
    Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...

  • Long-term depression
    Long-term depression
    Long-term depression , in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress...

  • Long-term memory
    Long-term memory
    Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

  • Actin remodeling of neurons
    Actin remodeling of neurons
    Actin remodeling is a biochemical process in cells. In the actin remodeling of neurons, the protein actin is part of the process to change the shape and structure of dendritic spines. G-actin is the monomer form of actin, and is uniformly distributed throughout the axon and the dendrite...


External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK