Fall Asleep While Learning About Long-term Potentiation

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Where I read random articles from across the web to bore you to sleep with my soothing voice.

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Benjamin Boster.

Today's episode is from a Wikipedia article titled,

Long-Term Potentiation.

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 Terry Ailomo 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.

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 Crunian 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,

And that memory could be new connections,

Or undergo metabolic and synaptic changes that enhance their ability to communicate and create a neural network of experiences.

Let us assume that the persistence of repetition of a reverberatory activity,

Or trace,

Tends to induce lasting cellular changes that add to its stability.

When an axon of cell A is near enough to excite a cell B,

And repeatedly or persistently takes part in firing it,

Some growth process or metabolic change takes place in one or both cells,

Such that A's efficiency,

As one of the cells firing B,

Is increased.

Eric Handel,

1964,

And associates were some of the first researchers to discover long-term potentiation during their work with sea slug aplesia.

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.

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 could not come until the later half of the 20th century,

At about the same time as the discovery of long-term potentiation.

LTP was first observed by Terje Lomo in 1966 in the Oslo,

Norway laboratory of Per Andersen.

There,

Lomo conducted a series of neurophysiological experiments on anesthetized rabbits to explore the role of hippocampus in short-term memory.

Lomo's experiments focused on connections or synapses from the perframed brain to the brain stem cells in the hippocampus.

Lomo's experiments focused on connections or synapses from the perframed pathway to the dentate gyrus.

These experiments were carried out by stimulating presynaptic fibers of the perframed 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 perframed pathway caused excitatory postsynaptic potentials,

EPSPs,

In cells of the dentate gyrus.

What Lomo unexpectedly observed was that the postsynaptic cell's 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 excited stronger prolonged EPSPs in the postsynaptic cell population.

This phenomenon,

Whereby a high-frequency stimulus could produce a long-lived enhancement in the postsynaptic cell's response to subsequent single-pulse stimuli,

Was initially called long-lasting potentiation.

Timothy Bliss,

Who joined the Anderson Laboratory in 1968,

Collaborated with Lomo,

And in 1973,

The two published the first characterizations 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 Lomo report.

In 1975,

Douglas and Goddard proposed long-term potentiation as a new name for the phenomenon of long-lasting potentiation.

Anderson suggested that the authors chose long-term potentiation perhaps because of its easily pronounced acronym LTP.

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 rearranging or synchronizing the relationship between receptor regulation,

LTP,

And synaptic strength.

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 signaling 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 depend only in part upon the anatomic location in which LTP is observed.

For example,

LTP in the chaffer 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 post-synaptic activity required to induce LTP are often 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 post-synaptic depolarization of cells.

Non-Hebbian LTP requires simultaneous pre- and post-synaptic depolarization for its induction.

Non-Hebbian LTP is a type of LTP that does not require such simultaneous depolarization of pre- and post-synaptic 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 pre-synaptic depolarization and relative post-synaptic 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.

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 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 titanic 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.

Maintenance While induction entails a transient activation of CAMKII and PKC,

Maintenance of ELTP,

Early form LTP,

Is characterized by their persistent activation.

During this stage,

PKMζ,

Which does not have dependence on calcium,

Become autonomously active.

Consequently,

They are able to carry out the phosphorylation events that underlie ELTP expression.

Expression Phosphorylation is a chemical reaction in which a small phosphate 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 ELTP.

First and most importantly,

They phosphorylate existing AMPA receptors 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 ELTP is independent of protein synthesis.

This is achieved by having a non-synaptic pool of AMPA receptors adjacent to the postsynaptic membrane.

When the appropriate LTP-inducing stimulus arrives,

Non-synaptic 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 ELTP 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 in the postsynaptic cell during ELTP may lead to the synthesis of a retrograde messenger.

According to this hypothesis,

The newly synthesized messenger travels across the synaptic cleft from the postsynaptic to the presynaptic cell.

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 postsynaptic cell may also undergo an increase in neurotransmitter vesicle number.

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 LTP,

L-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 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 and protein synthesis 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 factors 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,

A persistently active kinase that is L-LTP-protein kinase,

A persistently active kinase whose synthesis increases following LTP induction.

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,

While most recent evidence points to cell adhesion proteins.

Before the local protein synthesis hypothesis gained significant support,

There was general agreement that the protein synthesis underlying LLTP occurred in the cell body.

Further,

There was thought that the products of this synthesis were shipped cell-wide in a non-specific 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 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 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 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,

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 synthesis of a synaptic tag.

Simultaneous strong stimulation of a synaptic tag 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.

Simultaneity 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.

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.

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 is not a modulator.

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 estradiol may enhance LTP by driving Krebs phosphorylation and subsequent dendritic spine growth.

Nitric oxide synthase activity may also result in the subsequent activation of guanylyl cyclase and PKG.

Similarly,

Activation of dopamine receptors may enhance LTP through the KAMP-PKA signaling pathway.