In
neuroscience
Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developme ...
, synaptic plasticity is the ability of
synapses to
strengthen or weaken over time, in response to increases or decreases in their activity. Since
memories
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...
are postulated to be represented by vastly interconnected
neural circuits in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, synaptic plasticity is one of the important neurochemical foundations of
learning and
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
(''see
Hebbian theory
Hebbian theory is a neuroscientific theory claiming that an increase in synaptic efficacy arises from a presynaptic cell's repeated and persistent stimulation of a postsynaptic cell. It is an attempt to explain synaptic plasticity, the adaptation ...
'').
Plastic change often results from the alteration of the number of
neurotransmitter receptors located on a synapse.
There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of
neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters. Synaptic plasticity in both
excitatory
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
and
inhibitory
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...
synapses has been found to be dependent upon
postsynaptic
Chemical synapses are biological junctions through which neurons' signals can be sent 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 sys ...
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
release.
Historical discoveries
In 1973,
Terje Lømo and
Tim Bliss first described the now widely studied phenomenon of
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 ...
(LTP) in a publication in the ''Journal of Physiology''. The experiment described was conducted on the synapse between the
perforant path
In the brain, the perforant path or perforant pathway provides a connectional route from the entorhinal cortex to all fields of the hippocampal formation, including the dentate gyrus, all CA fields (including CA1), and the subiculum.
Though it ...
and
dentate gyrus
The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute t ...
in the
hippocampi of anaesthetised rabbits. They were able to show a burst of tetanic (100 Hz) stimulus on perforant path fibres led to a dramatic and long-lasting augmentation in the post-synaptic response of cells onto which these fibres synapse in the dentate gyrus. In the same year, the pair published very similar data recorded from awake rabbits. This discovery was of particular interest due to the proposed role of the hippocampus in certain forms of memory.
Biochemical mechanisms
Two molecular mechanisms for synaptic plasticity involve the
NMDA
''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...
and
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
glutamate receptors. Opening of NMDA channels (which relates to the level of cellular
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
) leads to a rise in post-synaptic Ca
2+ concentration and this has been linked to long-term potentiation, LTP (as well as to protein
kinase activation); strong depolarization of the post-synaptic cell completely displaces the
magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...
ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg
2+ ions, resulting in less Ca
2+ entering the post-synaptic neuron and lower intracellular Ca
2+ concentrations (which activate protein phosphatases and induce
long-term depression
In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depen ...
, LTD).
These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g.
AMPA receptors), improving cation conduction, and thereby potentiating the synapse. Also, these signals recruit additional receptors into the post-synaptic membrane, stimulating the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels.
The second mechanism depends on a
second messenger cascade regulating
gene transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...
and changes in the levels of key proteins at pommel synapses such as
CaMKII
/calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the /calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator ...
and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the
dendritic spine
A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical s ...
. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the
plasma membrane and phosphorylation of ion channels for enhanced permeability.
[
] Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells.
[
] This second mechanism can be triggered by
protein phosphorylation but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these
second messengers.
Phosphodiesterase
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many ot ...
, for example, breaks down the secondary messenger
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron .
Long-lasting changes in the efficacy of synaptic connections (
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 ...
, or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit of
activin A
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
, are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the
MAP-kinase pathway. By changing the
F-actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
structure of dendritic spines, spine necks are lengthened producing increased electrical isolation. The end result is long-term maintenance of LTP.
The number of
ion channels on the post-synaptic membrane affects the strength of the synapse. Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron's excitability in response to stimuli. In a dynamic process that is maintained in equilibrium,
N-methyl D-aspartate receptor (NMDA receptor) and AMPA receptors are added to the membrane by
exocytosis and removed by
endocytosis.
[
][
] These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity.
Experiments have shown that AMPA receptors are delivered to the synapse through vesicular
membrane fusion
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
with the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation.
When there is high-frequency NMDA receptor activation, there is an increase in the expression of a protein
PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
that increases synaptic capacity for AMPA receptors.
[
] This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity.
If the strength of a synapse is only reinforced by stimulation or weakened by its lack, a
positive feedback loop
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...
will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and
metaplasticity Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of ''individual'' synapses. However this new form re ...
, also exist to provide
negative feedback.
Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.
Synaptic scaling serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small
excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
s in response to continual excitation and raising them after prolonged blockage or inhibition.
This effect occurs gradually over hours or days, by changing the numbers of
NMDA receptors at the synapse (Pérez-Otaño and Ehlers, 2005).
Metaplasticity Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of ''individual'' synapses. However this new form re ...
varies the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD (
long-term depression
In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depen ...
) rely on the influx of
Ca2+ through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery.
Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs.
The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn.
There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such as
exocytosis of AMPA receptors is spatially regulated by the
t-SNARE
SNARE proteins – " SNAP REceptor" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells,
and some numbers in plants. The primary role of SNARE proteins is to mediate vesicle ...
STX4
Syntaxin-4 is a protein that in humans is encoded by the ''STX4'' gene.
Interactions
STX4 has been shown to interact with:
* Gelsolin,
* NAPA,
* RAB4A,
* SNAP-25,
* SNAP23,
* STXBP1,
* STXBP5,
* Syntaxin binding protein 3,
* TXLNB, ...
. Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium.
The spatial gradient of PKA between dendritic spines and shafts is also important for the strength and regulation of synaptic plasticity.
It is important to remember that the biochemical mechanisms altering synaptic plasticity occur at the level of individual synapses of a neuron. Since the biochemical mechanisms are confined to these "microdomains," the resulting synaptic plasticity affects only the specific synapse at which it took place.
Theoretical mechanisms
A bidirectional model, describing both LTP and LTD, of synaptic plasticity has proved necessary for a number of different learning mechanisms in
computational neuroscience
Computational neuroscience (also known as theoretical neuroscience or mathematical neuroscience) is a branch of neuroscience which employs mathematical models, computer simulations, theoretical analysis and abstractions of the brain to u ...
,
neural networks, and
biophysics
Biophysics is an interdisciplinary science that applies approaches and methods traditionally used in physics to study biological phenomena. Biophysics covers all scales of biological organization, from molecular to organismic and populations. ...
. Three major hypotheses for the molecular nature of this plasticity have been well-studied, and none are required to be the exclusive mechanism:
# Change in the probability of glutamate release.
# Insertion or removal of post-synaptic AMPA receptors.
#
Phosphorylation and de-phosphorylation inducing a change in AMPA receptor conductance.
Of these, the latter two hypotheses have been recently mathematically examined to have identical calcium-dependent dynamics which provides strong theoretical evidence for a calcium-based model of plasticity, which in a linear model where the total number of receptors are conserved looks like
:
where
*
is the
synaptic weight of the
th input axon,
*