Long term depression(A guide)

In this article, we will present long term depression, its main characteristics, you can also read about mechanisms that weaken synapses, as well as some research about changes of the brain caused by long term depression.

What is long-term depression?

Long-term depression (LTD) is a decrease in the efficiency of neuronal synapses dependent on activity.

It lasts for hours or longer after a prolonged stimulation pattern.

LTD is found in areas of the central nervous system with various mechanisms depending on the area of the brain and development.

Long term depression is one of some processes that serve to selectively weaken attenuate specific synapses in order to use the synaptic amplification caused by LTP constructively.

This is necessary because, if we allow a further increase in strength, the synapses, as a result, will reach the ultimate level of efficiency, which will prevent the coding of new information.

Characteristics of Long Term Depression

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

It has also been found that LTD is found in various types of neurons that secrete various neurotransmitters.

However, the most common neurotransmitter involved in LTD is L-glutamate. L-glutamate acts on N-methyl-D-aspartate receptors (NMDAR), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR), kainate receptors (KARs), and metabotropic glutamate receptors (mGluRs) during LTD.

This may be the result of intense synaptic stimulation (as occurs in Purkinje cerebellum cells) or constant weak synaptic stimulation (as in the hippocampus).

Long-term potentiation (LTP) is the opposite process, too long term depression (LTD); this is a lasting increase in synaptic strength.

In combination, LTD and LTP are factors that influence the synaptic plasticity of neurons.

Long term depression is believed to be the result of mainly a decrease in the density of postsynaptic receptors, although a decrease in the release of presynaptic neurotransmitters may also play a role.

Cerebellar LTD is believed to be essential for motor training. However, it is likely that other ductility mechanisms also play a role.

Hippocampal LTD may be essential for cleaning old memory traces.

Hippocampal/cortical LTD may be dependent on NMDA receptors, metabotropic glutamate receptors (mGluRs), or endocannabinoids.

The result of the underlying molecular mechanism of LTD is the phosphorylation of AMPA glutamate receptors and their elimination from the surface of the parallel synapse of Purkinje cells (PF-PC). 

Mechanisms that Weaken Synapses

Cerebellum

Although LTP plays a significant role in the associative type of learning that occurs in the hippocampus and neocortex, LTD is a significant player in error-based learning that occurs in the cerebellar cortex.

Recent studies have identified the complex signaling processes underlying LTD.

In the long run, long term depression can result in loss of synapses or in the form of silent synapses, which have recently been found to predominate in the cerebellar cortex.

LTD is found in synapses in the neurons of the cerebellum Purkinje, which receive two forms of stimulating input, one of the only climbing fibers and one of hundreds of thousands of parallel fibers.

Long term depression reduces the efficiency of parallel transmission at the synapses of the fiber, although, according to the latest data, it also degrades the transmission at the synapses of the upstream fiber.

Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur.

However, concerning the release of calcium, it is best if parallel fibers are activated several hundred milliseconds before the fibers rise.

In one way, the 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 is depolarized.

The binding of glutamate to the metabotropic receptor activates phospholipase C (PLC) and produces secondary messengers of diacylglycerol (DAG) and inositol triphosphate (IP3).

In a pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-controlled ion channels, increasing intracellular calcium levels.

Together, DAG and IP3 increase the increase in calcium concentration, targeting IP3-sensitive receptors that trigger the release of calcium from intracellular stores, as well as the activation of protein kinase C (PKC) (which is carried out jointly by calcium and DAG).

PKC phosphorylates AMPA receptors, which contributes to their dissociation from framework proteins in the postsynaptic membrane and subsequent internalization.

With the loss of AMPA receptors, the postsynaptic response of Purkinje cells to the release of glutamate from parallel fibers is reduced.

The triggering of calcium in the cerebellum is a critical mechanism for prolonged depression.

Parallel fiber terminals and curly fibers work together in a positive feedback loop to provide high calcium release.

Hippocampus

Long term depression affects the hippocampal synapses between the Schaffer collaterals and the CA1 pyramidal cells.

The LTD in the synapses of the Colaffer-CA1 Schaffer depends on the time and frequency of the influx of calcium.

Long term depression occurs at these synapses when Schaffer collaterals are repeated over long periods (10-15 minutes) at a low frequency (approximately 1 Hz).

Depressive excitatory postsynaptic potentials (EPSPs) are the result of this particular simulation model.

The magnitude of the calcium signal in the postsynaptic cell largely determines whether LTD or LTP occurs; LTD is caused by a small, slow increase in postsynaptic calcium.

When the Ca2 + input is below a threshold, this results in an LTD. The threshold level in CA1 is located on a sliding scale, which depends on the history of the synapse.

If the synapse has already undergone LTP, the threshold rises, increasing the likelihood that calcium influx will lead to long term depression.

In this way, the negative feedback system supports synaptic plasticity. 

Activation of NMDA receptors, which belong to the class of ionotropic glutamate receptors (iGluR), is necessary for the entry of calcium into the CA1 postsynaptic cell.

The voltage change provides a gradual control of postsynaptic Ca2 + by regulating the NMDAR-dependent Ca2 + influx, which is responsible for initiating LTD.

While LTP is partially due to the activation of protein kinases, which subsequently phosphorylate the target proteins, LTD is due to the activation of calcium-dependent phosphatases, which dephosphorylate the target proteins.

Selective activation of these phosphatases due to changes in calcium levels may be responsible for the various calcium effects observed during LTD.

[2] Activation of postsynaptic phosphatases induces the internalization of synaptic AMPA receptors (also of the iGluR type) into postsynaptic cells using clathrin-coated endocytosis mechanisms, thereby reducing the sensitivity to glutamate released by the Schaffer collateral terminals.

Long Term Depression Research

Research on the role of LTD in neurological disorders such as Alzheimer’s disease (AD) is ongoing.

It has been suggested that a decrease in NMDAR-dependent LTD may be associated with changes not only in postsynaptic AMPARs, but also in NMDAR, and these changes may be present in early and mild forms of Alzheimer’s type dementia. 

Also, researchers recently discovered a new mechanism (which includes LTD) that binds soluble amyloid-beta protein (Aβ) with synaptic damage and memory loss associated with AD.

Although the role of Aβ in the regulation of LTD was not clearly understood, it was found that soluble Aβ contributes to LTD of the hippocampus and is mediated by a decrease in glutamate recycling in the hippocampal synapses.

An excess of glutamate is thought to contribute to the progressive loss of neurons in AD.

Evidence that soluble Aβ enhances LTD through a mechanism involving altered glutamate uptake in the hippocampal synapses is essential for the initiation of synaptic deficiency in AD and types of age-related accumulation of Aβ.

This study provides a new understanding of the development of AD and offers potential therapeutic targets for this disease.

Further research is needed to understand how soluble amyloid-beta specifically affects glutamate transporters. 

Research How Long Term Depression Changes the Brain

Researchers from the Center for Addiction and Mental Health (CAMH) in Ontario, Canada, wanted to find out if life with long term depression over ten years will affect the brain, and if so, how.

They compared the brain scans of people who had lived with depression over ten years with those of people with a shorter history of depression.

The researchers from CAMH worked with 80 people aged 18–75. Twenty-five of them lived with depression for more than ten years, 25 – less than ten years, and 30 – without depression.

This last group made up the control group. In research in 2015, Dr. Meyer and his colleagues saw that during significant depression episodes, human brains would show inflammation signs.

Basing on that, researchers wanted to study if brain inflammation worsened by time in people with long term depression.

Dr. Meyer and his team determined the severity of the inflammation through positron emission tomography (PET).

This allowed them to control the activity of microglia, the type of cells found in the central nervous system that are associated with an inflammatory response to damage.

Active microglia produce translocation protein (TSPO), which is a crucial marker of inflammation.

Through a PET scan, Dr. Meyer and his colleagues found that the concentration of TSPO in the brain of people who had been living with depression for more than ten years was 29–33 percent higher.

The mentioned markers of inflammation were found, in particular, in three areas of the brain: the prefrontal cortex, the anterior cingulate gyrus, and the islet.

Recommended books and sources

1. HFNE “Adderall for Depression”
2. HFNE “Agitated Depression”
3. The Cognitive Behavioral Workbook for Depression: A Step-by-Step Program (A New Harbinger Self-Help Workbook)
4. The Depression and Anxiety Cure: A Guide Toward Simple and Natural Long-Term Solutions for Stress-Free Living
5. The Upward Spiral: Using Neuroscience to Reverse the Course of Depression, One Small Change at a Time
6. Video – 2-Minute Neuroscience: Long-Term Depression (LTD)
7. You Can Do All Things: Drawings, Affirmations, and Mindfulness to Help With Anxiety and Depression

Conclusion

Thus, discussing the topic “Long term depression,” we learned that long term depression (LTD) is a decrease in efficiency of neuronal synapses dependent on activity.

It lasts for hours or longer after a prolonged stimulation pattern.

Long term depression is one of some processes that serve to selectively weaken attenuate specific synapses in order to use the synaptic amplification caused by LTP constructively. 

Cerebellar LTD is believed to be essential for motor training.

However, it is likely that other ductility mechanisms also play a role; for example, hippocampal LTD may be essential for cleaning old memory traces.

A group of researchers found that the concentration of TSPO in the brain of people who had been living with depression for more than ten years was 29–33 percent higher.

However, more researches are needed to find out how long term depression affects the brain.

Please feel free to comment on the content or ask any questions in the comments section below.

References

1. How LTD alters the brain
2. Learn more about long term depression