Metaplasticity
Encyclopedia
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 synapse
s. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in memory
and learning
such as Long-term potentiation
(LTP), Long-term Depression
(LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamine
s, and the pool of hormone
s affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured hippocampus
cells or hippocampal slices.
is “plastic”, meaning it can be moulded and formed. This plasticity
is what allows you to learn throughout your lifetime ; your synapses change based on your experience. New synapses can be made, old ones destroyed, or existing ones can be strengthened or weakened. The original theory of plasticity is called “Hebbian plasticity”, named after Donald Hebb in 1949. A quick but effective summary of Hebbian theory is that “cells that fire together, wire together”, together being the key word here which will be explained shortly. Hebb described an early concept of the theory, not the actual mechanics themselves. Hebbian plasticity involves two mechanisms: LTP and LTD, discovered by Bliss and Lomo in 1973. LTP, or long-term potentiation, is the increase of synapse sensitivity due to a prolonged period of activity in both the presynaptic and postsynaptic neuron
. This prolonged period of activity is normally concentrated electric impulses, usually around 100 Hz. It is called “coincidence” detection in that it only strengthens the synapse if there was sufficient activity in both the presynaptic and postsynaptic cells. If the postsynaptic cell does not become sufficiently depolarized then there is no coincidence detection and LTP/LTD do not occur. LTD, or long-term depression, works the same way however it focuses on a lack of depolarization coincidence. LTD can be induced by electrical impulses at around 5 Hz. These changes are synapse specific. A neuron can have many different synapses all controlled via the same mechanisms defined here.
The earliest proposed mechanism for plastic activity is based around glutamate receptor
s and their ability to change in number and strength based on synapse activity. Glutamate has two main receptor types: AMPA
and NMDA
. These are named after drugs that bind to the receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate, respectively) however they all bind glutamate. When a glutamatergic synapse releases glutamate it binds to both the AMPA and the NMDA receptors. The AMPA receptors are ionotropic receptors that are responsible for fast synaptic transmission. In a nutshell the NMDA receptors evoke a response in the cell only when sufficient glutamate has been transmitted to cause that cell to depolarize enough to unblock the NMDA receptor. Sufficient depolarization in the membrane will cause the magnesium cation blockade in the NMDA receptors to vacate, thus allowing calcium influx into the cell. NMDA receptors are "coincidence" detectors. They determine when the presynaptic and postsynaptic neuron are linked in time via activity. When this occurs, NMDA receptors become the control mechanism that dictates how the AMPA and NMDA receptors are to be rearranged. The rearrangement of AMPA and NMDA receptors has become the central focus of current studies of metaplasticity as it directly determines LTP and LTD thresholds. There is large amounts of research focused on finding the specific enzymes and intracellular pathways involved in the NMDAR-mediated modulation of membrane AMPA receptors. Recent biochemical research has shown that a deficiency in the protein tenascin-R (TNR) leads to a metaplastic increase in the threshold for LTP induction. TNR is an extracellular-matrix protein expressed by oligodendrocytes during myelination .
or LTD
respectively. Prolonged low-frequency stimulation (5 Hz, the method used to induce LTD) can move an active synapse to depressed and then silent. However, synapses that have just become active cannot be depressed or silenced. Thus there is state-machine-like behavior at the synapse when it comes to transitions. However, the states themselves can have varying degrees of intensity. One active-state synapse can be stronger than another active-state synapse. This is, in theory, how you can have a strong memory vs. a weak memory. The strong memories are the ones with very heavily populated active synapses, while weak memories may still be active but poorly populated with AMPARs. The same research has shown that NMDA receptors themselves, once thought to be the control mechanism behind AMPA receptor organization, can be regulated by synaptic activity . This regulation of the regulation mechanism itself adds another layer of complexity to the biology of the brain.
s. Gliotransmitters include glutamate, ATP, and, more recently, the amino acid D-serine. Once thought to be glycine itself, D-serine serves as a ligand in the glycine site of NMDARs. D-serine is synthesized by astrocytes and is heavily co-localized with NMDARs. Without D-serine there can be no NMDA-induced neurotoxicity, or almost any NMDA response of any kind. Due to this evidence it is clear that D-serine is an essential ligand for the NMDA receptors. An essential factor in this research is the fact that astrocytes will vary their coverage of neurons based on the physiological processes of the body. Oxytocin and vasopressin neurons will have more NMDA receptors exposed due to astrocyte activity during lactation than during normal functioning. This research took place mostly in cells from the hypothalamic supraoptic nucleus, or SON. Due to synaptic plasticity being almost completely dependent on NMDAR processing, dynamic astrocyte NMDAR coverage is by nature a metaplasticity parameter .
manages synaptic connections across the entire cell in an attempt to keep them at manageable connection levels. Hebbian methods tend to drive networks into either a maximized state or a minimized state of firing, thus limiting the potential activity and growth of the network. With homeostatic mechanisms in place there is now a sort of "gain control" which allows these Hebbian methods to be checked in order to maintain their information processing abilities . This kind of modulation is important to combat intense lack of neural activity, such as prolonged sensory deprivation (in this study in particular it is light-deprivation affecting visual cortex neurons) or damage caused by stroke. Synaptic scaling is a mechanism in place to hold synapse sensitivity at normalized levels. Prolonged periods of inactivity increase the sensitivity of the synapses so that their overall activity level can remain useful. Chronic activity causes desensitization of the receptors, lowering overall activity to a more biologically manageable level. Both AMPA and NMDA receptor levels are affected by this process and so the overall “weight” of each synaptic connection (refined by Hebbian methods) is maintained while still increasing the overall level of activity over the entire neuron. It has been shown that both the presynaptic and the postsynaptic neuron are involved in the process, changing the vesicle turnover rate and AMPA receptor composition respectively .
Recent research has found that the calcium-dependent enzyme CaMKII, which exists in an alpha and beta isoform, is key in inactivity-dependent modulation. A low alpha/beta ratio causes an increased threshold for cellular excitation via calcium influx and thus favors LTP .
s.
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...
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...
. Until that time synaptic plasticity had referred to the plastic nature of individual synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in 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....
and 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...
such as Long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP), 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...
(LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s, and the pool of hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured 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...
cells or hippocampal slices.
Hebbian Plasticity
The brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
is “plastic”, meaning it can be moulded and formed. This plasticity
Plasticity
Plasticity may refer to:Science* Plasticity , in physics and engineering, plasticity is the propensity of a material to undergo permanent deformation under load...
is what allows you to learn throughout your lifetime ; your synapses change based on your experience. New synapses can be made, old ones destroyed, or existing ones can be strengthened or weakened. The original theory of plasticity is called “Hebbian plasticity”, named after Donald Hebb in 1949. A quick but effective summary of Hebbian theory is that “cells that fire together, wire together”, together being the key word here which will be explained shortly. Hebb described an early concept of the theory, not the actual mechanics themselves. Hebbian plasticity involves two mechanisms: LTP and LTD, discovered by Bliss and Lomo in 1973. LTP, or long-term potentiation, is the increase of synapse sensitivity due to a prolonged period of activity in both the presynaptic and postsynaptic 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...
. This prolonged period of activity is normally concentrated electric impulses, usually around 100 Hz. It is called “coincidence” detection in that it only strengthens the synapse if there was sufficient activity in both the presynaptic and postsynaptic cells. If the postsynaptic cell does not become sufficiently depolarized then there is no coincidence detection and LTP/LTD do not occur. LTD, or long-term depression, works the same way however it focuses on a lack of depolarization coincidence. LTD can be induced by electrical impulses at around 5 Hz. These changes are synapse specific. A neuron can have many different synapses all controlled via the same mechanisms defined here.
The earliest proposed mechanism for plastic activity is based around glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s and their ability to change in number and strength based on synapse activity. Glutamate has two main receptor types: AMPA
AMPA
AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
and NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
. These are named after drugs that bind to the receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate, respectively) however they all bind glutamate. When a glutamatergic synapse releases glutamate it binds to both the AMPA and the NMDA receptors. The AMPA receptors are ionotropic receptors that are responsible for fast synaptic transmission. In a nutshell the NMDA receptors evoke a response in the cell only when sufficient glutamate has been transmitted to cause that cell to depolarize enough to unblock the NMDA receptor. Sufficient depolarization in the membrane will cause the magnesium cation blockade in the NMDA receptors to vacate, thus allowing calcium influx into the cell. NMDA receptors are "coincidence" detectors. They determine when the presynaptic and postsynaptic neuron are linked in time via activity. When this occurs, NMDA receptors become the control mechanism that dictates how the AMPA and NMDA receptors are to be rearranged. The rearrangement of AMPA and NMDA receptors has become the central focus of current studies of metaplasticity as it directly determines LTP and LTD thresholds. There is large amounts of research focused on finding the specific enzymes and intracellular pathways involved in the NMDAR-mediated modulation of membrane AMPA receptors. Recent biochemical research has shown that a deficiency in the protein tenascin-R (TNR) leads to a metaplastic increase in the threshold for LTP induction. TNR is an extracellular-matrix protein expressed by oligodendrocytes during myelination .
Synaptic States
Research in 2004 has shown that synapses do not strengthen or weaken on a sliding scale. There are discrete states that synapses move between. These states are active, silent, recently-silent, potentiated, and depressed. The states which they can move to are dependent on the state that they are in at the moment. Thus, the future state is determined by the state gained by previous activity. For instance, silent (but not recently-silent) synapses can be converted to active via the insertion of AMPARs in the postsynaptic membrane. Active synapses can move to either potentiated or depressed via LTPLTP
- Science and technology :* Lunar Transient Phenomena, a short-lived change in appearance of Earth's moon* Long-tailed pair, a differential pair amplifier* Lightweight Telephony Protocol, a signaling protocol...
or LTD
LTD
- Business and finance :*Ltd. or Ltd, denotes a business incorporated under the laws of England, Wales, Scotland, Canada, other Commonwealth countries, the Republic of Ireland, Cyprus, Israel and some Anglophone countries in Africa, like Ghana or Nigeria....
respectively. Prolonged low-frequency stimulation (5 Hz, the method used to induce LTD) can move an active synapse to depressed and then silent. However, synapses that have just become active cannot be depressed or silenced. Thus there is state-machine-like behavior at the synapse when it comes to transitions. However, the states themselves can have varying degrees of intensity. One active-state synapse can be stronger than another active-state synapse. This is, in theory, how you can have a strong memory vs. a weak memory. The strong memories are the ones with very heavily populated active synapses, while weak memories may still be active but poorly populated with AMPARs. The same research has shown that NMDA receptors themselves, once thought to be the control mechanism behind AMPA receptor organization, can be regulated by synaptic activity . This regulation of the regulation mechanism itself adds another layer of complexity to the biology of the brain.
Synaptic Tagging
Recent research has found a mechanism known as "synaptic tagging". When new receptor proteins are being expressed and synthesized they must also be transported to the synaptic membrane, and some sort of chemical messaging is required for this. Their research has shown that activation of cAMP/PKA signaling pathways is required for LTP induction due to its "tagging" nature. It was even shown that simple pharmacological activation of cAMP/PKA pathways was sufficient for the synapse to be tagged, completely independent of any sort of activity.NMDA Receptors
The NMDA receptor is made up of three subunits: NR1, a variable NR2 subunit, and a variable NR3 subunit. Two NR2 subunits in particular have been the subject of intense study: NR2A and NR2B. The NR2B subunit not only is more sensitive to glutamate and takes longer to desensitize, but also allows more calcium entrance into the cell when it opens. A low NR2A/NR2B ratio is generally correlated with a decreased threshold of activation caused by rearing animals in light-deprived environments. This has been shown experimentally via light deprivation studies in which it was shown that the NR2A/B ratio declined. The threshold can be increased in some situations via light exposure. Studies of this nature were used to find the critical period for formation of the visual system in cats. This shifting ratio is a measurement of LTD/LTP threshold and thus has been posited as a metaplasticity mechanism .Gliotransmitters
Glial cells not only provide structural and nutritional support for neurons, but also provide processing support via chemicals known as gliotransmitterGliotransmitter
Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells and are usually induced from Ca2+ signaling. [3] While gliotransmitters can be released from any glial cell, including oligodendrocytes, astrocytes, and microglia,...
s. Gliotransmitters include glutamate, ATP, and, more recently, the amino acid D-serine. Once thought to be glycine itself, D-serine serves as a ligand in the glycine site of NMDARs. D-serine is synthesized by astrocytes and is heavily co-localized with NMDARs. Without D-serine there can be no NMDA-induced neurotoxicity, or almost any NMDA response of any kind. Due to this evidence it is clear that D-serine is an essential ligand for the NMDA receptors. An essential factor in this research is the fact that astrocytes will vary their coverage of neurons based on the physiological processes of the body. Oxytocin and vasopressin neurons will have more NMDA receptors exposed due to astrocyte activity during lactation than during normal functioning. This research took place mostly in cells from the hypothalamic supraoptic nucleus, or SON. Due to synaptic plasticity being almost completely dependent on NMDAR processing, dynamic astrocyte NMDAR coverage is by nature a metaplasticity parameter .
Synaptic Homeostasis
Homeostatic plasticityHomeostatic plasticity
In Neuroscience, homeostatic plasticity refers to the capacity of neurons to regulate their own excitability relative to network activity, a compensatory adjustment that occurs over the timescale of days....
manages synaptic connections across the entire cell in an attempt to keep them at manageable connection levels. Hebbian methods tend to drive networks into either a maximized state or a minimized state of firing, thus limiting the potential activity and growth of the network. With homeostatic mechanisms in place there is now a sort of "gain control" which allows these Hebbian methods to be checked in order to maintain their information processing abilities . This kind of modulation is important to combat intense lack of neural activity, such as prolonged sensory deprivation (in this study in particular it is light-deprivation affecting visual cortex neurons) or damage caused by stroke. Synaptic scaling is a mechanism in place to hold synapse sensitivity at normalized levels. Prolonged periods of inactivity increase the sensitivity of the synapses so that their overall activity level can remain useful. Chronic activity causes desensitization of the receptors, lowering overall activity to a more biologically manageable level. Both AMPA and NMDA receptor levels are affected by this process and so the overall “weight” of each synaptic connection (refined by Hebbian methods) is maintained while still increasing the overall level of activity over the entire neuron. It has been shown that both the presynaptic and the postsynaptic neuron are involved in the process, changing the vesicle turnover rate and AMPA receptor composition respectively .
Recent research has found that the calcium-dependent enzyme CaMKII, which exists in an alpha and beta isoform, is key in inactivity-dependent modulation. A low alpha/beta ratio causes an increased threshold for cellular excitation via calcium influx and thus favors LTP .
Endocannabinoid Metaplasticity
Research in 2004 has shown that endocannabinoid release from the postsynaptic neuron can inhibit activation of the presynaptic neuron. Type 1 canabbinioid receptors (CB1Rs) are the receptors on the presynaptic neuron responsible for this effect. The specific ligand is thought to be 2-arachidonyl glycerol, or 2-AG. This has mainly been found in GABAergic synapses and thus has been termed inihibitory long term depression (I-LTD). This effect has been found to be extremely localized and accurate, meaning the cannabinoids do not diffuse far from their intended target. This inhibition primes the synapses for future LTP induction and is thus metaplastic in nature .Neuronal adaptation mechanism
A new mechanism has been proposed that concerns the innate excitability of a neuron. It is quantified by the size of the hyperpolarization in mV due to K+ channels re-opening during an action potential. After any sort of learning task, particularly a classical or operant conditioning task, the amplitude of the K+ hyperpolarization, or "after hyperpolarization (AHP)", is greatly reduced. Over time this AHP will return to normal levels. This normalization does not correlate with a loss of memory but instead a loss of learning potential.Digital Metaplasticity
Digital Metaplasticity is a specific quality which defines methods that apply plastic art languages to digital symbolic systemSymbolic system
In the fields of anthropology, sociology, and psychology, symbolic system refers to a system of interconnected symbolic meanings. In particular, the field focuses on the dynamic relationships between various symbols within different task or theoretical contexts...
s.