Long-term potentiation, or LTP, is the mechanism by which our memories are created and stored. It allows us to store memories by changing the structure of the synapses (connections between neurons) and remodeling the brain. Increasing LTP can help us improve our learning capabilities and memory. Read this post to learn more about LTP and how to increase it.

Long-Term Potentiation Basics

Our brains are composed of 100 billion neurons that send information to each other through junctions called synapses. Our brains can change and adapt by strengthening the connections at existing synapses or by creating new synapses directly with other neurons.

Synaptic plasticity is the ability of a synapse to strengthen or weaken over time. It is the reason we can learn new skills and remember them.

Long-term potentiation, or LTP for short, is one of the most important processes responsible for synaptic plasticity.

LTP increases the strength of a synapse by increasing its activity for a prolonged period of time. It makes it easier for information to be transferred at the synapse. This is how we store long-term memories and learn new traits [1, 2].

It has been observed in various parts of the brain such as the cerebellum, cerebral cortex, amygdala, and hippocampus [2].

LTP happens when neurons are excited, a role that is typically carried out by glutamate. Glutamate is the main excitatory neurotransmitter in the brain and contributes significantly to the formation of memories and learning [3].

LTP was originally discovered in the hippocampus, a part of the brain that is involved in learning and memory, spatial navigation, and emotion. Neurons from the hippocampus connect with neurons of the amygdala, the primary brain center for processing emotions. That is why certain memories make you feel happy or sad [4, 5].

When two neurons communicate continuously, they become sensitized and more responsive to stimuli. It’s almost as if the neurons remember that they were previously stimulated, and they become easier to excite. The increase in excitability lasts from hours to days. The synapse is therefore said to be stronger because it can carry impulses easier [1, 2].

Long-Term Potentiation Requires Maintenance

LTP occurs in three main steps [1]:

  • Induction
  • Expression
  • Maintenance

The first two steps, induction and expression, are the initial stages of LTP. They correlate to short-term memories. They happen when you learn something new, like perhaps during a lecture. That is the beginning of long-term potentiation. Without maintenance, you probably won’t be able to recall this information in a few days.

When you sit at home and study this information, over time the pathways are activated again and the memories become consolidated. This occurs because of increases in proteins that will actually change the shape of neurons to accommodate the information.

This is the process of maintenance, and it allows us to store information for years at a time within a single neuronal pathway [6].

Factors That Impair Long-Term Potentiation

Abnormal long-term potentiation is a cause and a side effect of many different conditions.

1) Drugs of Abuse

Different substances like opiates, amphetamines, and cocaine can produce long-lasting changes in the strength of synapses. This leads to fond memories of abuse and subsequent addiction [7].

2) Neurodegenerative Diseases

Alzheimer’s and Parkinson’s are marked by structural changes that impair LTP and decrease our ability to function and remember properly [8, 9].

Melatonin can inhibit long-term potentiation via melatonin receptors (MT2) and is implicated in the development of Alzheimer’s [10].

However, melatonin is also an antioxidant that can decrease the effects of harmful chemicals in the body (reactive oxidative species), which aids in LTP formation [11].

3) Anxiety and Stress

Constant stress increases LTP in the amygdala. However, this increase is harmful, because it causes structural changes in the neurons that raise our susceptibility to fear. These long-term changes can result in persistent anxiety disorders [12, 13].

4) Depression

Patients with depression have dysfunctional LTP, which results in a harmful structural change in the brain. This creates persistent negative memories that contribute to the formation of mood disorders [14].

5) Schizophrenia

Patients with schizophrenia often have cognitive deficits. This is caused by impaired LTP in the hippocampus [15].

6) Sleep Deprivation

Not getting more than 6 hours of sleep a night causes impairments in the maintenance stage of LTP, making it harder to remember information over time [16].

Sleep deprivation in pregnant rats resulted in emotional and cognitive deficits in the offspring [17].

7) Autism

Induction of LTP is impaired in patients with autism [18].

8) Epilepsy

Patients with epilepsy and recurrent seizures often report issues with memory and learning, which is the result of faulty long-term potentiation [19].

9) High-Fat Diet

Eating high amounts of fat is linked to impairments in memory and learning. This is caused by the presence of palmitic acid, a fatty acid commonly seen in high-fat diets [20].

Ways to Increase Long-Term Potentiation

There are a number of scientifically proven methods to increase long-term potentiation in our brains.

1) Fasting

Dietary restriction can have profound effects on the brain. To prevent low blood sugar, the brain is rewired during fasting [21].

During fasting, structural changes are seen in the neurons that are responsible for regulating hunger. These include increases in the size of the neurons and synaptic excitability [22, 23].

This is attributed to the activity of proteins that maintain the changes of LTP [23].

Caloric restriction in mice improved cognitive function. This was mediated by increases in glutamate activity, resulting in improved LTP. Intermittent fasting may be even able to reverse age-related cognitive decline [24].

2) Berberine

Berberine is a supplement that is found naturally in a variety of plants. It is mostly used to aid in diabetes and blood sugar control but is also an antioxidant [25].

Patients with diabetes often have learning and memory issues. This was prevented in diabetic rats by the use of berberine. It improved synapse function and increased neuron survival [25].

3) Lipoic Acid

Lipoic acid is involved in many metabolic processes in the body. It is also produced as a supplement and is primarily used as an antioxidant.

In a mouse model of Alzheimer’s disease, lipoic acid increased the availability of glucose, the main energy source in the brain, and improved brain function. It increased LTP in mice with impaired synaptic plasticity, which is the underlying cause of memory dysfunction in patients with Alzheimer’s [26].

In a group of rats that were exposed to lead poisoning, lipoic acid was able to protect the brain and reverse the impairments in long-term potentiation [27].

High-fat diets are linked to improper brain function and harm long-term potentiation. When supplemented with lipoic acid, mice fed a high-fat diet were protected from a loss of LTP and decreased brain activity [28].

4) Luteolin

Luteolin is a flavonoid found in broccoli, celery, artichokes, rosemary, and oregano [29].

It can heal rat brains that were damaged by lack of oxygen and nutrients. It does so by recovering LTP and improving the firing of neurons [30].

Luteolin mediates most of its beneficial effects by increasing specific proteins involved in the late phase of LTP. It is currently being investigated as a potential agent to treat neurodegenerative diseases that are characterized by memory loss [30].

5) Ginseng

One of the main components of ginseng, gintonin, activates LTP in the mouse brain (hippocampus). Ginseng also contains a number of lysophosphatidic acids (LPAs) that support the induction of LTP. This is done by binding to LPA receptors, which are implicated in synaptic plasticity [31].

6) Ashwagandha

Ashwagandha can improve brain function and memory in people who have suffered from injuries. The mechanism is not known, but it is possible that its antioxidant properties contribute to this benefit [32, 33].

Ashwagandha improved spatial memory in epileptic rats. It was able to restore the number of NMDA receptors, which are crucial for long-term potentiation [34].

7) Fisetin

Fisetin is another plant-based flavonoid found in onions, cucumbers, and strawberries.

It improves long-term memory through a number of different mechanisms. Specifically, it activates certain proteins (ERK’s, CREB) that mediate late-phase LTP and increase protein production, which is required for long-term structural changes in the brain [35].

Object recognition in mice was improved after supplementation with fisetin [35].

8) Glycine

Glycine is an important inducer of long-term potentiation and is even used experimentally to study the characteristics of LTP.

It binds to the NMDA receptor, exciting the neuron and increasing its activity. Glycine receptors and transporters are also fundamental to LTP. Chemicals that block glycine activity prevent LTP, indicating that glycine is necessary for this process [36, 37].

Supplementing glycine improved the negative symptoms of schizophrenia in rats, and this may have been by increasing long-term potentiation [36].

9) Forskolin

Forskolin is a plant-derived compound. It works by activating the enzyme adenylyl cyclase, leading to a rise in the protein cyclic AMP (cAMP). When this protein increases, it can activate the late phase of LTP [38].

In rats that were oxygen deprived, forskolin supplementation prevented memory loss by increasing blood flow to the brain [39].

Forskolin supplements may be able to improve your memory and are gaining popularity online. However, it has not been studied in humans as a memory or learning enhancer.

10) Taurine

Taurine restored LTP in chemically damaged rat hippocampal brain slices. It improved the activity of the neurons and the transfer of information. It does this by improving the energy use within the cell [40].

However, it can only strengthen synapses in the presence of calcium. Taurine increases the amount of active CREB protein, which is important for late-phase LTP to occur [41].

In rats suffering from lead poisoning, taurine supplementation was able to restore the synaptic activity and improve cognitive function [42].

11) Ginkgo Biloba

Ginkgo biloba extracts improved spatial memory and learning in aged rats and mice. It increases the excitability of the neurons and the early phase of LTP [43, 44].

It is also thought to improve cognitive function in patients with dementia by directly interacting with the glutamate system [45].

12) Curcumin

Curcumin is the main component of turmeric. It reversed spatial memory deficits in patients with HIV-1. This is due to its neuroprotective capabilities and ability to restore brain function (including LTP) after damage [46].

Similarly, curcumin in aged rats and rats with Alzheimer’s disease restored memory by improving connections between neurons [47].

13) Creatine

When given to pregnant female rats, creatine supplementation improved the function of hippocampal neurons in the offspring. It increased the firing of the neurons, neuron excitability, and LTP maintenance [48].

Creatine supplementation has not been studied for safety in pregnant women.

14) Erythropoietin

Erythropoietin stimulates the production of red blood cells. However, it also plays a role in brain organization, learning, and memory. Chronic exposure to erythropoietin is linked to the improved excitability of neurons (LTP) [49].

15) Glucose

Glucose is the main form of energy in the brain. It increases cognitive function in the hippocampus. However, glucose uptake into the cells is dependent on insulin [50].

Balance is important when it comes to both glucose and insulin levels.

Insulin promotes LTP in rat brain, but elevated insulin levels are linked to deficits in cognitive function [51, 52, 53].

Also, both low and high glucose can impair cognitive function [54].

16) Bacopa

Bacopa monnieri significantly increased LTP in rats by increasing levels of proteins required for synaptic plasticity. It reversed amnesia in rats treated with drugs that cause cognitive impairments and amnesia by blocking LTP [55, 56].

17) Exercise (In Moderation)

Exercise plays a very important role in keeping us healthy and maintaining proper brain function. It improved synaptic plasticity and long-term potentiation in rats. However, this effect is reversible and will decrease if exercise is not maintained [57, 58].

Similarly, in a rat model of Alzheimer’s disease, exercise in the form of daily moderate treadmill activity was able to improve the deficits seen in LTP [59].

However, high-intensity training in mice resulted in cognitive dysfunction and impaired LTP by increasing inflammation in the brain (hippocampus) [60].

Long-Term Depression

As opposed to long-term potentiation, the efficiency of information transfer between neurons can actually be decreased at specific synapses by a process called long-term depression, or LTD. Basically, long-term depression weakens synapses [61].

It has many of the same characteristics of LTP, and it causes long-lasting changes in the synapse, from hours to days [61].

Under healthy conditions, LTD is a normal part of synaptic plasticity that aids in the storage of information. It is our way of letting certain memories decay so that we can learn new things and prioritize other information. LTD is also a fundamental part of the way we learn new motor skills [61, 1].

However, LTD is increased abnormally in some diseases like Alzheimer’s, Parkinson’s, multiple sclerosis, and diabetes. It is also suspected to play a role in the development of drug addiction [62, 63].

Similarly, we see increased levels of LTD in the brain during periods of acute stress, which explains why you sometimes can’t recall information well when panicking [62].

How LTP Works

NMDA-receptor dependent LTP is the most well-researched form of long-term potentiation. This is how it works [64]:

LTP occurs in 2 main phases, which can be thought of as the learning process and then the memory consolidation process.

Early Phase LTP (learning)

  • Glutamate binds to NMDA receptors and excites the neuron. This dislodges Mg2+ ions that block the channel. Removal of the Mg2+ allows for calcium to enter the cell.
  • Calcium ions flow into the cell and activate protein kinase C (PKC) and calmodulin/calcium-dependent protein kinase II (CaMKII).
  • PKC and CaMKII activity increases the number of receptors at the membrane. The more receptors that are present at the surface, the more activity can occur at the neuron.
  • AMPA receptors are increased and activated to improve conductivity. This allows more positive ions like calcium and sodium to enter the cell. As the cell becomes more positive, the more excited it becomes and is able to fire more impulses.

Late Phase LTP (consolidation)

  • All of the activity of early phase long-term potentiation continues but now more proteins are being created. These include more receptors to mediate LTP, structural proteins, and proteins that promote cell survival and health.
  • CaMKII and PKC activate ERKs.
  • ERKs increase protein production, which changes the structure of the neuron.
  • Another important protein, CREB, activates genes that assist in maintaining the new shape of the synapse.
  • All of the above results in changes in the overall structure and connectivity at the synapse.

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