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16 Strategies That May Stimulate Long-Term Potentiation (LTP)

Written by Puya Yazdi, MD | Last updated:
Biljana Novkovic
Matt Carland
Medically reviewed by
Biljana Novkovic, PhD, Matt Carland, PhD (Neuroscience) | Written by Puya Yazdi, MD | Last updated:

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In our previous post on long-term potentiation (LTP), we covered the basics of LTP and why it’s so important for healthy, optimal cognitive function.

We also discussed a variety of lifestyle, dietary, and other health-related factors that can interfere with how this important plasticity-related process is carried out in the brain.

If you missed that post, we highly recommend starting there first: you can find the post by clicking here.

With the basics of LTP out of the way, in this post, we’ll discuss some of the potential lifestyle factors and dietary supplements that have been proposed by researchers to have effects on LTP (and other critical plasticity-related brain processes).

Lifestyle, Dietary, And Other Factors That May Potentially Stimulate LTP

Before we move on to the main discussion, it’s important to note a few major limitations of the current science behind some of the factors and effects described in the sections below.

Firstly, the following potential effects of the substances and compounds listed below are based solely on animal- and cell-based studies, and are therefore “lacking evidence” from any appropriate human trials so far.

In other words, these are only potential “launching-points” for future clinical studies in humans, and no solid conclusions can be made about these compounds’ effects in humans until much more additional research is done.

Therefore, while some of these early results might seem promising, it is important to keep in mind that the evidence as a whole is still too weak to come to any definitive conclusions about these substances’ effects in healthy human users.

Secondly, much of the existing evidence from animal studies comes from studies of animals with specific health conditions – such as brain damage or experimentally-induced neurodegenerative disorders – or animals whose normal brain activity was interfered with by the administration of drugs or other toxins. Therefore, studies like these don’t necessarily establish that a given compound or substance would also have similar effects under normal, “healthy” conditions – at least, not without additional research.

As always, if you decide to try any new lifestyle or dietary changes, or experiment with supplements, it is extremely important to discuss them with your doctor first! This is critical because any such changes could have unexpected interactions with any pre-existing health conditions you may have – and only a qualified medical professional has the expertise and knowledge to help you navigate these potential concerns.

With all that in mind, let’s see what the latest science has to say about a variety of lifestyle, dietary, and supplement approaches that may potentially affect plasticity-related processes in the brain!

LACKING EVIDENCE:

1) Exercise

Exercise plays a very important role in keeping us healthy and maintaining proper brain function.

Some of exercises’ benefits may arise from its effects on LTP and other synaptic-plasticity-related mechanisms. For example, some preliminary animal studies have reported that exercise may significantly increase LTP and overall synaptic plasticity in rats. However, this effect was also seen to disappear if the rats stopped exercising regularly, suggesting that this effect would require consistent habitual exercise in order to be maintained [1, 2].

Relatedly, one other early study in animals reported that daily moderate exercise (in the form of treadmill-running) may potentially counteract some of the LTP-related deficits seen in a rat model of Alzheimer’s disease [3].

2) Fasting

Certain forms of fasting (“dietary restriction”) can have profound effects on the brain. For example, fasting may induce a form of synaptic plasticity (using neuropeptide Y) that helps counteract reduced glucose levels [4].

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 the excitability of their synapses [5, 6]. These changes have been attributed to the activity of proteins that maintain the changes of LTP [6].

According to one preliminary study in animals, caloric restriction in mice has been reported to improve cognitive function. This may be mediated by increases in glutamate activity, which could in turn result in the stimulation of LTP. Based on these early findings, some researchers have even proposed that intermittent fasting may even have the potential to prevent or reverse some forms of age-related cognitive decline [7] – although much more research in healthy human subjects will be needed to fully confirm this effect.

3) Berberine

Berberine is a natural nutritional compound that can be found in a variety of different plants. According to some preliminary research, berberine may have some potential as a treatment for diabetes (by helping regulate blood glucose levels). It may also have some anti-oxidant effects as well [8].

Interestingly, patients with diabetes frequently report cognitive issues, particularly with learning and memory. According to one animal study, berberine was reported to partially improve learning and memory functions in diabetic rats – possibly by stimulating LTP and overall synaptic plasticity in the hippocampus [8].

However, much more research would be needed to confirm these effects in ordinary human users of berberine.

4) Lipoic Acid

Lipoic acid is involved in many metabolic processes in the body. It is also sometimes used as a dietary supplement, due to its purported anti-oxidant effects.

According to one early animal study in mouse models of Alzheimer’s disease, lipoic acid was reported to increase the availability of glucose, which is the brain’s primary source of energy for its cells. This effect was, in turn, also reported to stimulate LTP and other important forms of synaptic plasticity, which is believed to be one of the main underlying mechanisms that may contribute to the memory deficits often observed in Alzheimer’s patients [9].

In another animal study, lipoic acid was reported to counteract impairments in LTP caused by lead poisoning in rats, suggesting a potential neuroprotective effect [10].

Relatedly, another factor which can impair brain function is eating a high-fat diet. According to one other animal study, lipoic acid was reported to protect against impairments in LTP induced by a high-fat diet in mice [11].

However, while these initial results seem promising, these effects have only been reported in animal studies so far. It is also important to note that these effects of lipoic acid were only observed in response to specific forms of toxicity or other brain impairments – and so it’s still not clear whether similar effects would also be seen in otherwise healthy animals. Much more research – especially in healthy human users – will be needed to fully confirm and extend these preliminary findings.

5) Luteolin

Luteolin is a natural flavonoid compound found in many plants, including broccoli, celery, artichokes, rosemary, and oregano [12].

According to one preliminary animal study, luteolin has been reported to partially counteract some of the brain damage caused by nutrient- and/or oxygen deprivation (hypoxia) in rats. The authors of this study propose that at least some of this effect may have been mediated by increased LTP potentially caused by the luteolin treatment [13].

The authors of this study also proposed that luteolin may have future potential as a possible treatment for the cognitive symptoms – such as memory impairments – seen in some neurodegenerative disorders [13]. However, this research is still in a very early stage, and much more study of this interesting flavonoid compound will be needed before it can be adopted as an official medical treatment.

6) Ginseng

One of the main active components in the herb ginseng is gintonin.

According to some preliminary data from animal and cell studies, gintonin may stimulate LTP and other synaptic-plasticity-related processes – particularly in hippocampal brain cells [14, 15].

Additionally, ginseng also contains a number of lysophosphatidic acids (LPAs). According to some preliminary studies in cells, LPAs may induce synaptic plasticity by binding to specialized receptors (LPA receptors) [14, 16].

However, these effects have not yet been directly observed in humans, so it’s not yet possible to come to any strong conclusions about the possible cognitive effects or potential mechanisms of ginseng in healthy human users.

7) Ashwagandha

Ashwagandha is an herb that has been reported to improve various aspects of brain function and cognition in patients with brain injuries. However, the potential mechanisms involved remain unknown.

Some researchers have proposed that these effects may arise from ashwagandha’s potential anti-oxidant effects [17, 18].

However, preliminary findings from one animal study in rats may suggest that this could be due to ashwagandha’s potential ability to increase the number of NMDA receptors in neurons, which are a major factor in stimulating (inducing) synaptic plasticity in brain cells [19].

However, much more research will still be needed to confirm ashwagandha’s potential cognitive effects, as well as what mechanisms might potentially be involved.

8) Fisetin

Fisetin is another plant-based flavonoid found in many plants, such as onions, cucumbers, and strawberries.

Some preliminary research suggests that fisetin may have an effect on memory function, likely through several different mechanisms. For example, some researchers have suggested that fisetin may play a role in activating certain proteins involved in “late-phase” LTP, such as ERK and CREB [20].

One early animal study reported that fisetin supplementation may have slightly improved object-recognition abilities in mice [20]. While this preliminary finding may suggest that fisetin supplementation could have some potential cognitive effects, much more research will be needed to find out what its exact effects might be in healthy human users.

9) Glycine

Glycine is an important amino acid that has been studied as a potential inducer of LTP in brain cells.

For example, cell studies have reported that chemicals that selectively block glycine also prevent LTP, suggesting that glycine activity may be crucial for stimulating synaptic plasticity in brain cells [21].

Although the exact mechanisms and pathways are still being researched, some early evidence suggests that glycine may act by binding to NMDA receptors, which in turn induce LTP in the neuron, thus increasing its activity. However, some other cell studies have reported that glycine’s role in LTP may be due to specialized glycine receptors [22].

It’s not yet known if glycine supplementation would have any significant effect in healthy human users. However, one early animal study has reported that glycine supplementation may partially improve some cognitive symptoms in a rat model of schizophrenia, and that this effect may involve increased LTP [22]. Nonetheless, much more research will still be needed to investigate this further.

10) Forskolin

Forskolin is a natural plant-derived compound that is believed to act in part by activating the enzyme adenylyl cyclase, which in turn increases levels of the protein cyclic AMP (cAMP) in the brain. cAMP is a protein that is known to be involved in some of the processes underlying “late-phase” LTP, thus suggesting that forskolin could potentially help induce or stimulate LTP [23].

According to one early animal study, forskolin supplementation was reported to partially counteract some of the memory deficits caused by oxygen deprivation (hypoxia) in rats. The authors of this study suggested that this may have been due both to stimulated LTP, as well as improved blood flow throughout the brain [24].

However, the potential effects and mechanisms of forskolin in healthy human users have not been extensively studied yet, and as such, it is not yet possible to come to any strong conclusions about its effectiveness as a “cognitive-enhancing” supplement.

11) Taurine

According to one preliminary study in cells, the essential amino acid taurine has been reported to partially help restore impaired LTP in rat hippocampal brain cells that were chemically damaged (exposed to neurotoxins) [25].

Similarly, one early animal study reported that taurine supplementation may help partially protect against impaired synaptic activity and cognitive functioning in rats suffering from lead poisoning [26].

Although the potential mechanisms involved are not yet known, some preliminary cell research suggests that taurine may act by increasing the levels of CREB, a protein that plays a significant role in “late-phase” LTP [27].

However, some other evidence suggests that taurine might only be able to affect synaptic plasticity in the presence of calcium [27].

Overall, much more research will still be needed to determine the potential effects of taurine on the brain, as well as if these effects also apply to ordinary healthy human users when taken as a supplement.

12) Ginkgo Biloba

According to a few preliminary animal studies, supplements and extracts from the herb Ginkgo biloba have been reported to potentially improve spatial memory and learning in aged rats and mice [28, 29].

However, the findings on these effects have been conflicting – and not every animal study of Ginkgo biloba’s cognitive effects has observed any noticeable or significant effects [30].

While the exact mechanisms are still unknown, some researchers have speculated that at least part of these potential effects may be due to the stimulation of “early-phase” LTP by some of Ginkgo’s active components [28, 29].

13) Curcumin

Curcumin is the main component of the common spice turmeric, and is widely used as a dietary health supplement.

According to one early animal study, curcumin supplementation has been reported to partially counteract some of the spatial memory deficits caused by the HIV-1 virus in rats. The authors of this study proposed that some of this effect may be due to the potential neuro-protective effects of curcumin, including increased LTP in damaged brain cells [31].

Additionally, a preliminary cell study reported that curcuminoids (compounds derived from curcumin) may help induce LTP in brain cells of rats with Alzheimer’s disease [32].

However, much more research will be needed to see if these effects might also apply to healthy human users who supplement with curcumin.

14) Glucose

Glucose is the main form of energy in the brain.

Due to this role, glucose is believed to play a major role in supporting a variety of cognitive functions – particularly in the hippocampus, a brain region widely known for its central role in learning and memory [33, 34].

However, the brain’s ability to use glucose effectively to power its cells is also highly dependent on the levels and activity of insulin [33].

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

For example, according to one animal study, insulin helps promote LTP in the brains of rats – but levels of insulin that are too high have also been linked to significant cognitive deficits [35, 36, 37].

Similarly, some evidence also suggests that both high- and low levels of glucose may impair cognitive functioning (possibly by interfering with LTP and other critical plasticity-related processes) [38].

15) Bacopa monnieri

The herb Bacopa monnieri has been reported to significantly increase LTP in rat brain cells [34].

Although the exact mechanisms are not yet fully understood, some researchers have proposed that bacopa may act by affecting the levels of various proteins required for inducing synaptic plasticity in neurons (such as calmodulin, protein kinase C, and pCREB) [39].

Bacopa has also been reported to partially counteract the memory impairment (amnesia) induced by other drugs, such as scopolamine, in rats [39].

However, because these studies only looked at isolated cells or animals whose normal brain activity was altered by other compounds, no strong conclusions can be made about bacopa’s potential cognitive effects in healthy animals or humans, and much more research will still be needed.

16) Erythropoietin

Erythropoietin is a hormone that stimulates the production of red blood cells (a process called erythropoiesis).

However, some researchers have also proposed that it may play a role in the brain, where it may affect certain cognitive processes related to learning and memory.

For example, one very preliminary cell study reported that chronically exposing neurons to erythropoietin was associated with increased cellular excitability, possibly suggesting LTP as a potential mechanism [40].

However, much more study in animals and humans will be needed to explore this hormone’s potential cognitive effects, and no solid conclusions can be made about them yet.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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