Long-term depression
Encyclopedia
Long-term depression in neurophysiology
, is an activity-dependent reduction in the efficacy of neuronal synapse
s lasting hours or longer. LTD occurs in many areas of the CNS
with varying mechanisms depending upon brain region and developmental progress. LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood. LTD has also been found to occur in different types of neurons that release various neurotransmitters. It can result from strong synaptic
stimulation (as occurs in the cerebellar
Purkinje cell
s) or from persistent weak synaptic stimulation (as in the hippocampus
). Long-term potentiation
(LTP) is the opposing process to LTD. LTD is thought to result mainly from a decrease in postsynaptic receptor
density, although a decrease in presynaptic neurotransmitter release may also play a role. Cerebellar LTD has been hypothesized to be important for motor learning
. However, it is likely that other plasticity mechanisms play a role as well. Hippocampal LTD may be important for the clearing of old memory traces.
Hippocampal/cortical LTD can be dependent on NMDA receptor
s, metabotrophic glutamate receptors (mGluR)
, or endocannabinoids.
LTD is one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP. This is necessary because, if allowed to continue increasing in strength, synapses would ultimately reach a ceiling level of efficiency, which would inhibit the encoding of new information.
, they would eventually come to the point of complete inactivity or too much activity. To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback
: metaplasticity
and scaling. Metaplasticity is expressed as a change in the capacity to provoke subsequent synaptic plasticity, including LTD and LTP
. The Bienenstock, Cooper and Munro model
(BCM model) proposes that a certain threshold exists such that a level of postsynaptic response below the threshold leads to LTD and above it leads to LTP. BCM theory further proposes that the level of this threshold depends upon the average amount of postsynaptic activity. Scaling has been found to occur when the strength of all of a neuron’s excitatory inputs are scaled up or down. LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function.
or heterosynaptic
. Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus. In other words, this form of LTD is activity-dependent, because the events causing the synaptic weakening occur at the same synapse that is being activated. Homosynaptic LTD is also associative in that it correlates the activation of the postsynaptic neuron with the firing of the presynaptic neuron. Heterosynaptic LTD, in contrast, occurs at synapses that are not potentiated or are inactive. The weakening of a synapse is independent of the activity of the presynaptic or postsynaptic neurons as a result of the firing of a distinct modulatory interneuron. Thus, this form of LTD impacts synapses nearby those receiving action potential
s.
synapses between the Schaffer collateral
s and the CA1 pyramidal cells. LTD at the Schaffer collateral-CA1 synapses depends on the timing and frequency of calcium influx. LTD occurs at these synapses when Schaffer collaterals are stimulated repetitively for extended time periods (10–15 minutes) at a low frequency (approximately 1 Hz). Depressed excitatory postsynaptic potentials (EPSPs)
result from this particular stimulation pattern. The type of calcium signal in the postsynaptic cell largely determines whether LTD or LTP
occurs; LTD is brought about by small, slow rises in postsynaptic calcium levels. When Ca2+ entry is below threshold, it leads to LTD. The threshold level in area CA1 is on a sliding scale that depends on the history of the synapse. If the synapse has already been subject to LTP, the threshold is raised, increasing the probability that a calcium influx will yield LTD. In this way, a "negative feedback" system maintains synaptic plasticity. Activation of NMDA-type glutamate receptors
, which belong to a class of ionotropic
glutamate receptors (iGluRs), is required for calcium entry into the CA1 postsynaptic cell. Change in voltage provides a graded control of postsynaptic Ca2+ by regulating NMDAR-dependent Ca2+ influx, which is responsible for initiating LTD.
While LTP is in part due to the activation of protein kinase
s, which subsequently phosphorylate target proteins, LTD arises from activation of calcium-dependent phosphatases that dephosphorylate the target proteins. Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD. The activation of postsynaptic phosphatases causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis
mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals.
Purkinje neurons
, which receive two forms of excitatory input, one from climbing fiber
s and one from parallel fiber
s. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission. Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. In one pathway, parallel fiber terminals release glutamate to activate AMPA
and metabotropic
glutamate receptors in the postsynaptic Purkinje cell. When glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptors, however, produces diacylglycerol (DAG) and inositol triphosphate (IP3
) second messengers
. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channel
s, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive triggering release of calcium from intracellular stores as well as protein kinase C (PKC
) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, causing receptor internalization as is seen in hippocampal LTD. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed.
. LTD is induced at corticostriatal medium spiny neuron
synapses in the dorsal striatum
by a high frequency stimulus coupled with postsynaptic depolarization, coactivation of dopamine D1
and D2
receptors and group I mGlu receptors, lack of NMDA receptor
activation, and endocannabinoid activation.
In the prelimbic cortex of the striatum
, three forms or LTD have been established. The mechanism of the first is similar to CA1-LTD: a low frequency stimulus induces LTD by activation of NMDA receptor
s, with postsynaptic depolarization and increased postsynaptic calcium influx. The second is initiated by a high frequency stimulus and is arbitrated by presynaptic mGlu receptor 2 or 3, resulting in a long term reduction in the involvement of P/Q-type calcium channels
in glutamate release. The third form of LTD requires endocannabinoids, activation of mGlu receptors, and repetitive stimulation of glutamatergic fibers (13 Hz for ten minutes) and results in a long term decrease in presynaptic glutamate release. It is proposed that LTD in GABAergic striatal neurons leads to a long term decrease in inhibitory effects on the basal ganglia
, influencing the storage of motor skills.
, and it is proposed to be involved in ocular dominance
. Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter
of the visual cortex causes LTD in layer III. In this form of LTD, low-frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic
. This type of LTD is similar to that found in the hippocampus
, because it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatases. LTD has also been found to occur in this fashion in layer II. A different mechanism is at work in the LTD that occurs in layer V. In layer V, LTD requires low frequency stimulation, endocannabinoid signaling, and activation of presynaptic NR2B-containing NMDA receptor
s.
It has been found that paired-pulse stimulation (PPS) induces a form of homosynaptic LTD in the superficial layers of the visual cortex
when the synapse is exposed to carbachol
(CCh) and norepinephrine
(NE).
The magnitude of this LTD is comparable to that which results from low frequency stimulation, but with fewer stimulation pulses (40 PPS for 900 low frequency stimulations). It is suggested that the effect of NE is to control the gain of NMDA receptor-dependent homosynaptic LTD. Like norepinephrine, acetylcholine
is proposed to control the gain of NMDA receptor-dependent homosynaptic LTD, but it is likely to be a promoter of additional LTD mechanisms as well.
is involved in LTD induction in the prefrontal cortex (PFC)
. The serotonin system in the PFC plays an important role in regulating cognition and emotion. Serotonin, in cooperation with a group I metabotropic glutamate receptor (mGluR) agonist, facilitates LTD induction through augmentation of AMPA receptor internalization. This mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in PFC neurons mediates.
in the perirhinal cortex
, and this prediction is confirmed by neurotransmitter receptor
blocking experiments. It is proposed that there are multiple memory mechanisms in the perirhinal cortex. The exact mechanisms are not completely understood, however pieces of the mechanisms have been deciphered. Studies suggest that one perirhinal cortex
LTD mechanism involves NMDA receptor
s and I and II mGlu receptors 24 hours after the stimulus. The other LTD mechanism involves acetylcholine receptor
s and kainate receptor
s at a much earlier time, about 20 to 30 minutes after stimulus.
function widely throughout the brain in presynaptic inhibition. Endocannabinoid retrograde signaling has been shown to effect LTD at corticostriatal
synapses and glutamatergic
synapses in the prelimbic cortex of the nucleus accumbens (NAc)
, and it is also involved in spike-timing-dependent LTD in the visual cortex
. Endocannabinoids are implicated in LTD of inhibitory inputs (LTDi) within the basolateral nucleus of the amygdala (BLA)
as well as in the stratum radiatum of the hippocampus. Additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor-dependent LTD in the hippocampus.
in which a millisecond-scale change in the timing of presynaptic and postsynaptic spikes will cause differences in postsynaptic Ca2+ signals, inducing either LTP
or LTD. LTD occurs when postsynaptic spikes precede presynaptic spikes by up to 20-50 ms. Whole-cell patch clamp
experiments "in vivo" indicate that post-leading-pre spike delays elicit synaptic depression.
LTP is induced when neurotransmitter release occurs 5-15 ms before a back-propagating action potential
, whereas LTD is induced when the stimulus occurs 5-15 ms after the back-propagating action potential. There is a plasticity window: if the presynaptic and postsynaptic spikes are too far apart (i.e., more than 15 ms apart), there is little chance of plasticity. The possible window for LTD is wider than that for LTP – although it is important to note that this threshold depends on synaptic history.
When postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. Postsynaptic spiking alleviates the Mg2+ block on NMDA receptors. The postsynaptic depolarization will subside by the time an EPSP occurs, enabling Mg2+ to return to its inhibitory binding site. Thus, the influx of Ca2+ in the postsynaptic cell is reduced. CB1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release.
STDP selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). This results in a sharpened signal-to-noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans.
and memory
. Cerebellar LTD is thought to lead to motor learning, and hippocampal LTD is thought to contribute to the decay of memory. However, recent studies have found that hippocampal LTD may not act as the reverse of LTP, but may instead contribute to spatial memory formation. Although LTD is now well characterized, these hypotheses about its contribution to motor learning and memory remain controversial.
Studies have connected deficient cerebellar LTD with impaired motor learning. In one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak LTD and consequently impaired motor learning. However the relationship between cerebellar LTD and motor learning has been seriously challenged. A study on rats and mice proved that normal motor learning occurs while LTD of Purkinje cell
s is prevented by (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588). Likewise, LTD in mice was disrupted using several experimental techniques with no observable deficits in motor learning or performance. These taken together suggest that the correlation between cerebellar LTD and motor learning may have been illusory.
Studies on rats have made a connection between LTD in the hippocampus
and memory
. In one study, rats were exposed to a novel environment, and homosynaptic
LTD in CA1 was observed. After the rats were brought back to their initial environment, LTD activity was lost. It was found that if the rats were exposed to novelty, the electrical stimulation required to depress synaptic transmission was of lower frequency than without novelty. When the rat was put in a novel environment, acetylcholine
was released in the hippocampus
from the medial septum fiber, resulting in LTD in CA1. Therefore, it has been concluded that acetylcholine
facilitates LTD in CA1.
LTD has been correlated with spatial learning in rats, and it is crucial in forming a complete spatial map. It suggested that LTD and LTP
work together to encode different aspects of spatial memory.
New evidence suggests that LTP works to encode space, whereas LTD works to encode the features of space. Specifically, it is accepted that encoding of experience takes place on a hierarchy. Encoding of new space is the priority of LTP
, while information about orientation in space could be encoded by LTD in the dentate gyrus
, and the finer details of space could be encoded by LTD in the CA1.
is believed to occur in the nucleus accumbens
(NAc). After chronic cocaine use, the amount of AMPA receptor
s relative to NMDA receptor
s decreases in the medium spiny neurons in the NAc shell. This decrease in AMPA receptor
s is thought to occur through the same mechanism as NMDR-dependent LTD, because this form of plasticity is reduced after cocaine use. During the period of cocaine
use, the mechanisms of LTD artificially occur in the NAc. As a consequence, the amount of AMPA receptor
s is ramped up in the NAc neurons during withdrawal
. This is possibly due to homeostatic synaptic scaling. This increase in AMPA receptor
s causes a hyperexcitability in the NAc neurons. The effect of this hyperexcitability is thought to be an increase in the amount of GABA
release from the NAc on the ventral tegmental area (VTA), making the dopaminergic
neurons in the VTA less likely to fire, and thus resulting in the symptoms of withdrawal
.
is ongoing. It has been suggested that a reduction in NMDAR-dependent LTD may be due to changes not only in postsynaptic AMPARs but also in NMDARs, and these changes are perhaps present in early and mild forms of Alzheimer-type dementia
.
Additionally, researchers have recently discovered a new mechanism (which involves LTD) linking soluble amyloid beta protein (Aβ) with the synaptic injury and memory loss related to AD. While Aβ's role in LTD regulation has not been clearly understood, it has been found that soluble Aβ facilitates hippocampal LTD and is mediated by a decrease in glutamate
recycling at hippocampal synapses. Excess glutamate is a proposed contributor to the progressive neuronal loss involved in AD. Evidence that soluble Aβ enhances LTD through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in AD and in types of age-related Aβ accumulation. This research provides a novel understanding of the development of AD and proposes potential therapeutic targets for the disease. Further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters.
The mechanism of long-term depression has been well characterized in limited parts of the brain. However, the way in which LTD affects motor learning
and memory
is still not well understood. Determining this relationship is presently one of the major focuses of LTD research.
Neurophysiology
Neurophysiology is a part of physiology. Neurophysiology is the study of nervous system function...
, is an activity-dependent reduction in the efficacy of neuronal 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 lasting hours or longer. LTD occurs in many areas of the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
with varying mechanisms depending upon brain region and developmental progress. LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood. LTD has also been found to occur in different types of neurons that release various neurotransmitters. It can result from strong synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
stimulation (as occurs in the cerebellar
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...
Purkinje cell
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s) or from persistent weak synaptic stimulation (as in the 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...
). 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) is the opposing process to LTD. LTD is thought to result mainly from a decrease in postsynaptic receptor
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...
density, although a decrease in presynaptic neurotransmitter release may also play a role. Cerebellar LTD has been hypothesized to be important for motor learning
Motor learning
Motor learning is a “relatively permanent” change, resulting from practice or a novel experience, in the capability for responding...
. However, it is likely that other plasticity mechanisms play a role as well. Hippocampal LTD may be important for the clearing of old memory traces.
Hippocampal/cortical LTD can be dependent on NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, metabotrophic glutamate receptors (mGluR)
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...
, or endocannabinoids.
LTD is one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP. This is necessary because, if allowed to continue increasing in strength, synapses would ultimately reach a ceiling level of efficiency, which would inhibit the encoding of new information.
Neural homeostasis
It is highly important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedbackPositive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
, they would eventually come to the point of complete inactivity or too much activity. To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
: metaplasticity
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 referred to the plasticity of the plasticity itself, thus...
and scaling. Metaplasticity is expressed as a change in the capacity to provoke subsequent synaptic plasticity, including LTD and LTP
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...
. The Bienenstock, Cooper and Munro model
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...
(BCM model) proposes that a certain threshold exists such that a level of postsynaptic response below the threshold leads to LTD and above it leads to LTP. BCM theory further proposes that the level of this threshold depends upon the average amount of postsynaptic activity. Scaling has been found to occur when the strength of all of a neuron’s excitatory inputs are scaled up or down. LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function.
General forms of LTD
Long-term depression can be described as either homosynapticHomosynaptic
Homosynaptic interactions are events that occur at the junctions where neurons meet. Homosynaptic events occur at a single synapse or group of synapses but do not involve interactions between synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
or heterosynaptic
Heterosynaptic
Heterosynaptic phenomena are events that occur at the junctions that form connections between neurons. A heterosynaptic phenomenon is one that involves interactions between separate synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
. Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus. In other words, this form of LTD is activity-dependent, because the events causing the synaptic weakening occur at the same synapse that is being activated. Homosynaptic LTD is also associative in that it correlates the activation of the postsynaptic neuron with the firing of the presynaptic neuron. Heterosynaptic LTD, in contrast, occurs at synapses that are not potentiated or are inactive. The weakening of a synapse is independent of the activity of the presynaptic or postsynaptic neurons as a result of the firing of a distinct modulatory interneuron. Thus, this form of LTD impacts synapses nearby those receiving action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s.
Hippocampus
LTD affects hippocampalHippocampus
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...
synapses between 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...
s and the CA1 pyramidal cells. LTD at the Schaffer collateral-CA1 synapses depends on the timing and frequency of calcium influx. LTD occurs at these synapses when Schaffer collaterals are stimulated repetitively for extended time periods (10–15 minutes) at a low frequency (approximately 1 Hz). Depressed excitatory postsynaptic potentials (EPSPs)
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...
result from this particular stimulation pattern. The type of calcium signal in the postsynaptic cell largely determines whether LTD or LTP
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...
occurs; LTD is brought about by small, slow rises in postsynaptic calcium levels. When Ca2+ entry is below threshold, it leads to LTD. The threshold level in area CA1 is on a sliding scale that depends on the history of the synapse. If the synapse has already been subject to LTP, the threshold is raised, increasing the probability that a calcium influx will yield LTD. In this way, a "negative feedback" system maintains synaptic plasticity. Activation of NMDA-type glutamate receptors
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
, which belong to a class of ionotropic
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
glutamate receptors (iGluRs), is required for calcium entry into the CA1 postsynaptic cell. Change in voltage provides a graded control of postsynaptic Ca2+ by regulating NMDAR-dependent Ca2+ influx, which is responsible for initiating LTD.
While LTP is in part due to the activation of 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...
s, which subsequently phosphorylate target proteins, LTD arises from activation of calcium-dependent phosphatases that dephosphorylate the target proteins. Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD. The activation of postsynaptic phosphatases causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis
Receptor-mediated endocytosis
Receptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...
mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals.
Cerebellum
LTD occurs at synapses in cerebellarCerebellum
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...
Purkinje neurons
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
, which receive two forms of excitatory input, one from climbing fiber
Climbing fiber
Climbing fibers are the name given to a series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata.These axons pass through the pons and enter the cerebellum via the inferior cerebellar peduncle where they form synapses with the deep cerebellar nuclei and...
s and one from parallel fiber
Parallel fiber
Parallel fibers arise from granule cells in the cerebellar cortex. They form excitatory synapses onto the dendrites of Purkinje cells ....
s. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission. Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. In one pathway, parallel fiber terminals release glutamate to activate AMPA
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...
and metabotropic
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
glutamate receptors in the postsynaptic Purkinje cell. When glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptors, however, produces diacylglycerol (DAG) and inositol triphosphate (IP3
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
) second messengers
Second messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channel
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....
s, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive triggering release of calcium from intracellular stores as well as protein kinase C (PKC
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...
) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, causing receptor internalization as is seen in hippocampal LTD. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed.
Striatum
The mechanisms of LTD differ in the two subregions of the striatumStriatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. LTD is induced at corticostriatal medium spiny neuron
Medium spiny neuron
The medium spiny neurons are a special type of inhibitory cells representing approximately 90% of the neurons within the corpus striatum of the basal ganglia. They play a key role in initiating and controlling movements of the body, limbs, and eyes....
synapses in the dorsal striatum
Dorsal striatum
The dorsal striatum, corpus striatum or striated body is a compound structure consisting of the caudate nucleus, and the lentiform nucleus...
by a high frequency stimulus coupled with postsynaptic depolarization, coactivation of dopamine D1
Dopamine receptor D1
Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.- Function :This gene encodes the D1 subtype of the dopamine receptor. The D1 subtype is the most abundant dopamine receptor in the central nervous system. This G-protein-coupled receptor stimulates...
and D2
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
receptors and group I mGlu receptors, lack of NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
activation, and endocannabinoid activation.
In the prelimbic cortex of the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, three forms or LTD have been established. The mechanism of the first is similar to CA1-LTD: a low frequency stimulus induces LTD by activation of NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, with postsynaptic depolarization and increased postsynaptic calcium influx. The second is initiated by a high frequency stimulus and is arbitrated by presynaptic mGlu receptor 2 or 3, resulting in a long term reduction in the involvement of P/Q-type calcium channels
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
in glutamate release. The third form of LTD requires endocannabinoids, activation of mGlu receptors, and repetitive stimulation of glutamatergic fibers (13 Hz for ten minutes) and results in a long term decrease in presynaptic glutamate release. It is proposed that LTD in GABAergic striatal neurons leads to a long term decrease in inhibitory effects on the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, influencing the storage of motor skills.
Visual cortex
Long-term depression has also been observed in the visual cortexVisual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
, and it is proposed to be involved in ocular dominance
Ocular dominance
Ocular dominance, sometimes called eye dominance or eyedness, is the tendency to prefer visual input from one eye to the other. It is somewhat analogous to the laterality of right or left handedness; however, the side of the dominant eye and the dominant hand do not always match...
. Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
of the visual cortex causes LTD in layer III. In this form of LTD, low-frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic
Homosynaptic
Homosynaptic interactions are events that occur at the junctions where neurons meet. Homosynaptic events occur at a single synapse or group of synapses but do not involve interactions between synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
. This type of LTD is similar to that found in the 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...
, because it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatases. LTD has also been found to occur in this fashion in layer II. A different mechanism is at work in the LTD that occurs in layer V. In layer V, LTD requires low frequency stimulation, endocannabinoid signaling, and activation of presynaptic NR2B-containing NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s.
It has been found that paired-pulse stimulation (PPS) induces a form of homosynaptic LTD in the superficial layers of the visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
when the synapse is exposed to carbachol
Carbachol
Carbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery...
(CCh) and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE).
The magnitude of this LTD is comparable to that which results from low frequency stimulation, but with fewer stimulation pulses (40 PPS for 900 low frequency stimulations). It is suggested that the effect of NE is to control the gain of NMDA receptor-dependent homosynaptic LTD. Like norepinephrine, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
is proposed to control the gain of NMDA receptor-dependent homosynaptic LTD, but it is likely to be a promoter of additional LTD mechanisms as well.
Prefrontal cortex
The neurotransmitter serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
is involved in LTD induction in the prefrontal cortex (PFC)
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
. The serotonin system in the PFC plays an important role in regulating cognition and emotion. Serotonin, in cooperation with a group I metabotropic glutamate receptor (mGluR) agonist, facilitates LTD induction through augmentation of AMPA receptor internalization. This mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in PFC neurons mediates.
Perirhinal cortex
Computational models predict that LTD creates a gain in recognition memory storage capacity over that of 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...
in the perirhinal cortex
Perirhinal cortex
Perirhinal cortex is a cortical region in the medial temporal lobe that is made up of Brodmann areas 35 and 36. In rats, it is located along and dorsal to the rhinal sulcus. It receives highly-processed sensory information from all sensory regions, and is generally accepted to be an important...
, and this prediction is confirmed 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...
blocking experiments. It is proposed that there are multiple memory mechanisms in the perirhinal cortex. The exact mechanisms are not completely understood, however pieces of the mechanisms have been deciphered. Studies suggest that one perirhinal cortex
Perirhinal cortex
Perirhinal cortex is a cortical region in the medial temporal lobe that is made up of Brodmann areas 35 and 36. In rats, it is located along and dorsal to the rhinal sulcus. It receives highly-processed sensory information from all sensory regions, and is generally accepted to be an important...
LTD mechanism involves NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s and I and II mGlu receptors 24 hours after the stimulus. The other LTD mechanism involves acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
s and kainate receptor
Kainate receptor
Kainate receptors, or KARs, are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from red algae Digenea simplex. KARs are less well...
s at a much earlier time, about 20 to 30 minutes after stimulus.
Role of endocannabinoids
Endocannabinoids affect long-lasting plasticity processes in various parts of the brain, serving both as regulators of pathways and necessary retrograde messengers in specific forms of LTD. In regard to retrograde signaling, endocannabinoid receptors (CB1)Cannabinoid receptor type 1
The cannabinoid receptor type 1, often abbreviated to CB1, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.-Expression:The CB1 receptor is...
function widely throughout the brain in presynaptic inhibition. Endocannabinoid retrograde signaling has been shown to effect LTD at corticostriatal
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
synapses and glutamatergic
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
synapses in the prelimbic cortex of the nucleus accumbens (NAc)
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...
, and it is also involved in spike-timing-dependent LTD in the visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
. Endocannabinoids are implicated in LTD of inhibitory inputs (LTDi) within the basolateral nucleus of the amygdala (BLA)
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.-...
as well as in the stratum radiatum of the hippocampus. Additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor-dependent LTD in the hippocampus.
Spike timing-dependent plasticity
Spike timing-dependent plasticity (STDP) refers to the timing of presynaptic and postynaptic action potentials. STDP is a form of neuroplasticityNeuroplasticity
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...
in which a millisecond-scale change in the timing of presynaptic and postsynaptic spikes will cause differences in postsynaptic Ca2+ signals, inducing either LTP
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...
or LTD. LTD occurs when postsynaptic spikes precede presynaptic spikes by up to 20-50 ms. Whole-cell patch clamp
Patch clamp
The patch clamp technique is a laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells. The technique can be applied to a wide variety of cells, but is especially useful in the study of excitable cells such as neurons, cardiomyocytes, muscle...
experiments "in vivo" indicate that post-leading-pre spike delays elicit synaptic depression.
LTP is induced when neurotransmitter release occurs 5-15 ms before a back-propagating action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
, whereas LTD is induced when the stimulus occurs 5-15 ms after the back-propagating action potential. There is a plasticity window: if the presynaptic and postsynaptic spikes are too far apart (i.e., more than 15 ms apart), there is little chance of plasticity. The possible window for LTD is wider than that for LTP – although it is important to note that this threshold depends on synaptic history.
When postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. Postsynaptic spiking alleviates the Mg2+ block on NMDA receptors. The postsynaptic depolarization will subside by the time an EPSP occurs, enabling Mg2+ to return to its inhibitory binding site. Thus, the influx of Ca2+ in the postsynaptic cell is reduced. CB1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release.
STDP selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). This results in a sharpened signal-to-noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans.
Motor learning and memory
Long-term depression has long been hypothesized to be an important mechanism behind motor learningMotor learning
Motor learning is a “relatively permanent” change, resulting from practice or a novel experience, in the capability for responding...
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....
. Cerebellar LTD is thought to lead to motor learning, and hippocampal LTD is thought to contribute to the decay of memory. However, recent studies have found that hippocampal LTD may not act as the reverse of LTP, but may instead contribute to spatial memory formation. Although LTD is now well characterized, these hypotheses about its contribution to motor learning and memory remain controversial.
Studies have connected deficient cerebellar LTD with impaired motor learning. In one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak LTD and consequently impaired motor learning. However the relationship between cerebellar LTD and motor learning has been seriously challenged. A study on rats and mice proved that normal motor learning occurs while LTD of Purkinje cell
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s is prevented by (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588). Likewise, LTD in mice was disrupted using several experimental techniques with no observable deficits in motor learning or performance. These taken together suggest that the correlation between cerebellar LTD and motor learning may have been illusory.
Studies on rats have made a connection between LTD in the 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...
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....
. In one study, rats were exposed to a novel environment, and homosynaptic
Homosynaptic
Homosynaptic interactions are events that occur at the junctions where neurons meet. Homosynaptic events occur at a single synapse or group of synapses but do not involve interactions between synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
LTD in CA1 was observed. After the rats were brought back to their initial environment, LTD activity was lost. It was found that if the rats were exposed to novelty, the electrical stimulation required to depress synaptic transmission was of lower frequency than without novelty. When the rat was put in a novel environment, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
was released in the 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...
from the medial septum fiber, resulting in LTD in CA1. Therefore, it has been concluded that acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
facilitates LTD in CA1.
LTD has been correlated with spatial learning in rats, and it is crucial in forming a complete spatial map. It suggested that LTD and LTP
LTP
- 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...
work together to encode different aspects of spatial memory.
New evidence suggests that LTP works to encode space, whereas LTD works to encode the features of space. Specifically, it is accepted that encoding of experience takes place on a hierarchy. Encoding of new space is the priority of LTP
LTP
- 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...
, while information about orientation in space could be encoded by LTD in 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...
, and the finer details of space could be encoded by LTD in the CA1.
Cocaine as a model of LTD in drug addiction
The addictive property of cocaineCocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
is believed to occur in the 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). After chronic cocaine use, the amount of 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 relative to NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s decreases in the medium spiny neurons in the NAc shell. This decrease in 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 is thought to occur through the same mechanism as NMDR-dependent LTD, because this form of plasticity is reduced after cocaine use. During the period of cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
use, the mechanisms of LTD artificially occur in the NAc. As a consequence, the amount of 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 is ramped up in the NAc neurons during withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
. This is possibly due to homeostatic synaptic scaling. This increase in 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 causes a hyperexcitability in the NAc neurons. The effect of this hyperexcitability is thought to be an increase in the amount of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
release from the NAc on the ventral tegmental area (VTA), making the dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
neurons in the VTA less likely to fire, and thus resulting in the symptoms of withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
.
Current research
Research on the role of LTD in neurological disorders such as Alzheimer's disease (AD)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...
is ongoing. It has been suggested that a reduction in NMDAR-dependent LTD may be due to changes not only in postsynaptic AMPARs but also in NMDARs, and these changes are perhaps present in early and mild forms of Alzheimer-type dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
.
Additionally, researchers have recently discovered a new mechanism (which involves LTD) linking soluble amyloid beta protein (Aβ) with the synaptic injury and memory loss related to AD. While Aβ's role in LTD regulation has not been clearly understood, it has been found that soluble Aβ facilitates hippocampal LTD and is mediated by a decrease in glutamate
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
recycling at hippocampal synapses. Excess glutamate is a proposed contributor to the progressive neuronal loss involved in AD. Evidence that soluble Aβ enhances LTD through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in AD and in types of age-related Aβ accumulation. This research provides a novel understanding of the development of AD and proposes potential therapeutic targets for the disease. Further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters.
The mechanism of long-term depression has been well characterized in limited parts of the brain. However, the way in which LTD affects motor learning
Motor learning
Motor learning is a “relatively permanent” change, resulting from practice or a novel experience, in the capability for responding...
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....
is still not well understood. Determining this relationship is presently one of the major focuses of LTD research.
See also
- Hebbian theoryHebbian theoryHebbian 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...
- BCM theoryBCM theoryBCM 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...
- Electrical synapseElectrical synapseAn electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic neurons known as a gap junction. At gap junctions, such cells approach within about 3.5 nm of each other, a much shorter...
- Excitatory postsynaptic potentialExcitatory postsynaptic potentialIn 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...
- Homeostatic plasticityHomeostatic plasticityIn 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....
- Inhibitory postsynaptic potentialInhibitory postsynaptic potentialAn inhibitory postsynaptic potential is a synaptic potential that decreases the chance that a future action potential will occur in a postsynaptic neuron or α-motoneuron...
- Long-term potentiationLong-term potentiationIn 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) - Spike timing dependent plasticitySpike timing dependent plasticitySpike-timing-dependent plasticity is a biological process that adjusts the strength of connections between neurons in the brain. The process adjusts the connection strengths based on the relative timing of a particular neuron's output and input action potentials...
(STDP) - Neural FacilitationNeural facilitationNeural facilitation, also known as paired pulse facilitation, is a concept in neuroscience where an increase in the postsynaptic potential is evoked by a second impulse....
(Short-term plasticity) - NeuroplasticityNeuroplasticityNeuroplasticity 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...
- Postsynaptic potentialPostsynaptic potentialPostsynaptic potentials are changes in the membrane potential of the postsynaptic terminal of a chemical synapse. Postsynaptic potentials are graded potentials, and should not be confused with action potentials although their function is to initiate or inhibit action potentials...
- Actin remodeling of neuronsActin remodeling of neuronsActin 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...