Long-term depression

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

As the opposing process to long-term potentiation (LTP), 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. Both LTD and LTP are forms of synaptic plasticity.

Characterisation

LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood.

Hippocampal/cortical LTD can be dependent on NMDA receptors, metabotropic glutamate receptors (mGluR), or endocannabinoids. The result of the underlying-LTD molecular mechanism in cerebellum is the phosphorylation of AMPA glutamate receptors and their elimination from the surface of the parallel fiber-Purkinje cell (PF-PC) synapse.

Neural homeostasis

It is highly important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, 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.

General forms of LTD

Long-term depression can be described as either homosynaptic plasticity or heterosynaptic plasticity. 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. 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). 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. 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 kinases, 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. LTD is involved in predictive control exerted by cerebellar circuitry and cerebellar reserve.

Ca²⁺ involvement

Further research has determined calcium's role in long-term depression induction. While other mechanisms of long-term depression are being investigated, calcium's role in LTD is a defined and well understood mechanism by scientists. High calcium concentrations in the post-synaptic Purkinje cells is a necessity for the induction of long-term depression. There are several sources of calcium signaling that elicit LTD: climbing fibres and parallel fibres which converge onto Purkinje cells. Calcium signaling in the post-synaptic cell involved both spatial and temporal overlap of climbing fibre induced calcium release into dendrites as well as parallel fibre induced mGluRs and IP3 mediated calcium release. In the climbing fibres, AMPAR-mediated depolarization induces a regenerative action potential that spreads to the dendrites, which is generated by voltage-gated calcium channels. Paired with PF-mediated mGluR1 activation results in LTD induction. In the parallel fibres, GluRs are activated by constant activation of the parallel fibres which indirectly induces the IP3 to bind to its receptor (IP3) and activate calcium release from intracellular storage. In calcium induction, there is a positive feedback loop to regenerate calcium for long-term depression. Climbing and parallel fibres must be activated together to depolarize the Purkinje cells while activating mGlur1s. Timing is a critical component to CF and PF as well, a better calcium release involves PF activation a few hundred milliseconds before CF activity. In this form of LTD, low-frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic.

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).

Perirhinal cortex

Computational models predict that LTD creates a gain in recognition memory storage capacity over that of LTP in the perirhinal cortex, and this prediction is confirmed by neurotransmitter receptor blocking experiments. In regard to retrograde signaling, cannabinoid receptors 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. Although endocannabinoid retrograde signaling has been shown to effect glutamatergic synapses, it can also effect GABAergic synapses with either hetero- or homosynaptic interactions.

Spike timing-dependent plasticity

Spike timing-dependent plasticity (STDP) refers to the timing of presynaptic and postsynaptic action potentials. STDP is a form of neuroplasticity 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. 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.

Astrocyte Aid in LTD

Previous research has strictly focused on the aspects of neuronal LTD, however, emerging studies have shown astrocyte contribution to LTD in tripartite synapses. Through release of gliotransmitters, astrocytes are able to modulate synaptic activity when extracellular calcium levels rise. Astrocytes are experimentally shown to be involved with NMDA receptor dependent LTD in the somatosensory cortex, hippocampus, prefrontal cortex, and VTA by releasing glutamate or D-serine (as gliotransmitters) post-endocannabinoid interaction. Studies have shown that astrocytes are required for STDP, as they are able to reuptake glutamate from synapses (passively) and exchanging molecules within synapses such as releasing ATP to increase the adenosine levels in synapses to prevent LTD and produce LTP. Some forms of STDP that occur with NMDA receptors and mGluRs have shown that astrocyte cooperation is necessary, especially on the synapses of parallel fibers onto Purkinje cells. Furthermore, experiments on pyramidal cells showed that spike-timing dependent LTD (t-LTD) is astrocyte dependent, with astrocytes needing intracellular calcium release as well as CB1 receptor activation via neural endocanabanoid release. Experimental reports also show that at different points of experimentation, astrocytic calcium release was modulated over various temporal differences, meaning that astrocytes sense the temporal difference and modify their own signaling. The reason as to how the astrocytic sensing is still to be discovered.

Other studies show that astrocytic calcium release and SNARE-dependent vesicle release is necessary for NMDAR dependent LTD. By using a calcium chelator, researchers were able to block astrocytic calcium release in hippocampal neurons, leading to the discovery that NMDAR dependent LTD was impaired in samples paired with the chelator. Another test to ensure the findings showed that knocking out IP3 type 2 receptors (primary receptor for astrocytic calcium mobilization) in mice impaired LTD with low frequency stimulation. SNARE machinery was found to release glutamate from astrocytes; when inhibiting this machinery, the communication between neurons and astrocytes mediated by glutamate were severed and the original low frequency stimulation method failed to produce significant LTD. It was also mentioned that astrocyte supported LTD was important for removal of AMPAR from the postsynaptic neurons.

When researchers tested p38α MAPK specifically, varying effects were seen. p38α MAPK has been implied to be a part of the LTD intercellular pathway as well as stress signaling. With various knockout experiments it was determined that astrocytic, not neuronal p38α MAPK was necessary for LTD, due to the fact that a knockout of neuronal p38α had no significant effect on LTD in hippocampal cultures. Although testing of SNARE machinery in astrocytes had been tested, further examination determined that p38α MAPK in astrocytes was shown to increase glutamate release during low frequency stimulation and therefore increase NMDAR-dependent LTD. To test in vivo, researchers gave mice a virus that either depleted neuronal or astrocytic p38α MAPK. Before the injection, mice were tested for freezing behavior by being shocked 5 times in a familiar area. Thirty days after the initial test, mice with the astrocytic virus showed the biggest fear response, which gave the conclusion that p38α deletion from astrocytes enhances long-term memory. 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 cells 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 plasticity (LTD) in CA1 was observed. 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. After chronic cocaine use, the amount of AMPA receptors relative to NMDA receptors decreases in the medium spiny neurons in the NAc shell. Studies show that NMDA receptors role in learning can be hindered by alcohol in three major regions: dorsal striatum, neocortex, and hippocampus. In particular, these studies show that LTD due to alcohol is found in the dorsal striatum and the hippocampus, with deficits in the neocortex being caused by white and grey-matter degradation. Although LTD in the dorsal striatum was found when exposed to high frequency stimulation, a simulation of alcohol tolerance and withdrawal resulted in LTP in the same region.

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.

In relation to Alzheimer's disease, the structural protein Tau, has been found to have certain effects on LTD. Although an argument is made that Tau is only found in axons as a structural supporter, and the misfolding of it progresses the pathophysiology of AD, there has been compelling evidence that shows Tau is also found in dendrites. One of the post translational modifications (PTMs) of Tau is phosphorylation, which the protein is reliant on to fold into its correct states -- meaning hyperphosphorylation (part of the pathophysiology of AD) can change folding dynamics and damage neurons. Although the full mechanism has not been discovered, it has been found that hyperphosphorylation in Tau has been seen to weaken synapses and facilitates LTD by aggregation. Furthermore, comparing different sizes of aggregate Tau oligomers had no difference in effect as they all inhibited LTP and facilitated LTD.

In the field of research of cerebellum disorders, auto-antigens are involved in molecular cascades for induction of LTD of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a mechanism of synaptic plasticity in the cerebellum. Anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD. This causes an impairment of restoration or maintenance of the internal model hold by the cerebellum and triggers cerebellar ataxias. These diseases are LTDpathies.

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.

Neurodegeneration

Neurodegenerative diseases research remains inconclusive as to the mechanisms that triggers the degeneration in the brain. New evidence demonstrates there are similarities between the apoptotic pathway and LTD which involves the phosphorylation/activation of GSK3β. NMDAR-LTD(A) contributes to the elimination of excess synapses during development. This process is downregulated after synapses have stabilized, and is regulated by GSK3β. During neurodegeneration, there is the possibility that there is deregulation of GSK3β resulting in 'synaptic pruning'. If there is excess removal of synapses, this illustrates early signs of neurodegeration and a link between apoptosis and neurodegeneration diseases.

See also

• Brodmann area 25
• Hebbian theory
• BCM theory
• Electrical synapse
• Excitatory postsynaptic potential
• Homeostatic plasticity
• Inhibitory postsynaptic potential
• Long-term potentiation (LTP)

• Short-term synaptic depression

• Spike timing dependent plasticity (STDP)
• Neural Facilitation (Short-term plasticity)
• Neuroplasticity
• Postsynaptic potential
• Actin remodeling of neurons

References

Further reading

External links