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Synaptogenesis: 9 Ways To Form New Synapses In The Brain

Synapses are considered connections between neurons (brain cells) that foster neuronal communication.  The word “synapse” is derived from the Greek term “synapsis” which roughly translates to “conjunction.”  Your brain cells communicate with other cells by sending chemical messages in the form of neurotransmitters or electrical signals; these are transmitted via the synapses.

If you have a lot of synapses, you likely have more neural flexibility and possibly a higher functioning brain than someone with a reduced synaptic density.  Those with low counts of synapses are thought to suffer from neurodegenerative disorders, cognitive impairment, and reduced intelligence compared to individuals with greater synaptic densities.  The higher your synaptic count, the easier it is for your brain to adapt to meet the demands of environmental stimuli.

Fortunately your brain is able to form new synapses on its own via a process called synaptogenesis.  Synaptogenesis is thought to “explode” during adolescence, and slowly diminishes as a person reaches their 20s.  During the final stages of brain development, a process called “synaptic pruning” has taken place – uprooting unused synapses and strengthening the most-used synaptic connections via long-term potentiation.

9 Ways To Form New Synapses (Synaptogenesis)

Those without fully developed brains may want to consider enhancing synaptogenesis to promote optimal neurocognitive development.  Even if you happen to be an adult with a fully mature and developed brain, and your synapses have been “pruned,” there’s some evidence to suggest that you may be able to form new ones.  Below are some strategies that may help you form new cortical synapses.

1. Enriched Environment

Those exposed to an enriched environment will likely end up with more synapses than those growing up in a standard or non-enriched environment.  Though most research analyzing the phenomenon of synaptogenesis has been conducted in rats, there is reason to think that many of the same methods may be effective in humans.  One study discovered that rats growing up in an enriched environment had nearly 25% more synapses than a control group.

A 25% increase means more overall neural connections and pathways.  If you have a developing brain and/or are looking out for your child with a developing brain, facilitating an enriched environment characterized by physical and social stimulation may promote synaptogenesis.  Environmental enrichment was noted to form new synapses between multiple types of neurons (including pyramidal and stellate).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23460346
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/14199261
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/4165855
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/15262214
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/4730268

2. Motor Learning

Learning new things is known to be healthy for the brain.  However, it seems as though not just any “learning” is capable of inducing synaptogenesis.  If you want to grow new synapses, you may need to engage in motor learning, or learning something new associated with a movement (e.g. juggling, table tennis, etc.).

In a rodent study, it was found that adult rats that had been given difficult acrobatic training experienced synaptogenesis, whereas rats assigned to a physical exercise task or inactivity failed to form new synapses.  When comparing the rats that exercised with those that remained sedentary, there was no significant difference in synaptic densities.  This suggests that exercise alone is probably not enough to form synapses.

Your brain needs to be forced to coordinate complex limb movements with a particular activity.  It doesn’t necessarily need to be acrobatic training, but if you’re an acrobat – you may be one step ahead of the game.  Each time you engage in motor learning (e.g. figuring out how to hit a specific shot in table tennis), new synapses likely form to facilitate this new skill.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC54366/
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11749086
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24304717

3. Phosphatide Precursors

A report published in 2009 suggests that phosphatide precursors likely promote the formation of new synapses.  Phosphatides are a key component of synaptic membranes, therefore researchers speculated that administration of phosphatide precursors (a substance that is biologically converted into phosphatide) may result in synaptogenesis.  An animal study investigated the effects of these phosphatide precursors on synaptic count.

  • Uridine: This is a “building block” for RNA and indirectly aids in the process of memory formation. Uridine may work in conjunction with choline to promote the formation of new synapses.
  • DHA: This omega-3 fatty acid is considered to be a “building block” for brain development. There is evidence that it can improve cognitive function and overall mental health.  You can get DHA in your diet via consumption of fatty fish, or omega-3 fatty acid supplementation like fish oil and krill oil.
  • Choline: This is a water-soluble essential nutrient that serves as a precursor to acetylcholine. Acetylcholine is necessary for synaptogenesis as well as a variety of other neurophysiological functions.  Perhaps the best source of choline is dietary consumption of lightly cooked eggs.

It was reported that when all three of these compounds were administered, levels of neural phosphatides increased.  Notable biomarkers for synaptogenesis including PSD-95 and synapsin-1 also increased.  As a result of the ability of these phosphatide precursors to promote synaptogenesis, they are being tested in a compound format for Alzheimer’s disease; individiuals with neurodegenerative diseases tend to have reductions in synaptic counts.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19400698

4. Novel Antidepressants

It is thought that antidepressant medications may induce a double-whammy of simultaneous neurogenesis (new brain cells) and synaptogenesis (new synapses).  It is already well-established that SSRIs can induce neurogenesis, but whether they also aid in the formation of new synapses remains unclear; especially in human populations.

Spadin: A new study has discovered that a novel antidepressant (currently being investigated) called “Spadin” increases synaptogenesis. Spadin is a novel antidepressant peptide that inhibits a potassium channel called “TREK-1.”  In rodent studies, administration of Spadin was found to increase multiple biomarkers of synaptogenesis including PSD-95 and synapsin-1.  Researchers later confirmed that following treatment with Spadin, the number of synapses in rodents significantly increased.

It is encouraging to learn that potentially new antidepressants may increase formation of new synapses.  Untreated chronic depression and long-term stress is documented as inhibiting synaptic formation, thus leading to impairment in cortical functioning.  While it isn’t known whether the barrage of currently-available antidepressants have the same synaptogenesis effect as Spadin, it is thought that they may protect existing synapses.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25598009

Ketamine: Most people are familiar with the NMDA receptor antagonist that is ketamine.  It is considered a “Schedule III” controlled-substance in the United States and is commonly utilized as a hypnotic and anesthetic.  In some cases the drug is used recreationally, but is considered one of the least addictive drugs and is therefore seldom abused.

Investigation has revealed that using ketamine may provide rapid-acting relief from depressive symptoms.  In fact, various formulations including a ketamine nasal spray for depression have been engineered and shown some promise.  Preliminary evidence suggests that ketamine’s unique mechanism of action is capable of inducing synaptogenesis.

It acts on a cellular signaling pathway called “mTOR” (target of rapamycin).  When the “mTOR” pathway is activated, synaptogenesis appears to increase in the prefrontal cortex.  Some publications have gone as far as to suggest that ketamine-induced synaptogenesis may be responsible for the bulk of its antidepressant efficacy.

NMDA Modulators: Other drugs are being engineered to act on NMDA (glutamate) similar to ketamine, without the psychomimetic effects.  In other words, pharmaceutical and biotech companies are attempting to isolate the antidepressant mechanisms from ketamine while eliminating the possibility of dissociative side effects such as hallucinations and/or delusions.  Due to the fact that ketamine is able to promote synaptogenesis, it wouldn’t be a stretch to assume that various other NMDA modulators have similar effects.

Note: On an unrelated note, it seems as though activation of mTOR may expedite the biological aging process.  Inhibition of mTOR is known to slow the aging process and reduce age-related disease.  Since ketamine and other NMDA modulators increase mTOR activity, a short-term synaptogenesis gain may not outweigh an expedited aging process.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25817855

5. Behavioral Change

Another way to grow new synapses is to change your behavior.  A study documented that female birds experienced behavior change when treated with testosterone.  Researchers noted that they experienced a 51% in synapses formed in a region of their forebrain nucleus called the “robustus archistriatalis” (RA).

The researchers suggested that the increase in size of synapses and number of vesicles per synapse was associated with behavioral change.  In this case, the behavioral changes were manipulated by researchers via administration of testosterone (making the birds sing deeper) and spring-like weather compared to fall-like weather.  While carryover from a bird study may not be applicable to humans, it still could be.

It is known that behavioral changes alter neural activation and pathways.  Learning a new motor skill is associated with synaptogenesis.  It is possible that altering behavior for a certain period of time, regardless of what causes the behavioral alteration (e.g. drugs, environment, etc.), synaptogenesis may ensue.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/3978452

6. Hormone Optimization

There is some evidence to suggest that hormonal increases can induce synaptogenesis.  Specifically, increasing testosterone levels in males may aid in the formation of new synapses, whereas increasing estradiol and progesterone in females may have the same effect.  Some studies suggest that reduced production of various sex-specific hormones can inhibit synaptogenesis.

Estradiol: Researchers have known that estradiol increases synaptic plasticity in the hippocampal region of female rats.  In a study published in 2013, it was reported that reduced estradiol levels resulted in loss of synapses.  Increases in estradiol levels increased synapse formation in the hippocampus of females.  Inhibition of estradiol production in males is thought to have no effect on synaptogenesis.

Progesterone: In a study conducted with rats, progesterone administration enabled synaptogenesis within a particular region of the hippocampus.  This synaptogenesis helped the rats with neural recovery following a stroke (global cerebral ischemia).

Testosterone:  Based on a study analyzing the effects of testosterone administration to animal models with multiple sclerosis (MS), the testosterone increased synaptogenesis.  It also helped preserve neurons within the cerebral cortex of mice.  The increase in synaptogenesis has been associated with improved excitatory synaptic function, which aids in cognitive function.  Testosterone-induced synaptogenesis was believed to improve spatial memory and information processing speed.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/3978452
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21308798
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23873366
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22956822
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25926772

7. Low-Level Laser Therapy

In a study published in 2015, it was discovered that transcranial low-level laser therapy (LLLT) stimulates the formation of new synapses.  Researchers initially tested low-level laser therapy based on the fact that traumatic brain injury (TBI) animal models improved with administration of near-infrared light to their head.  This near-infrared light reduces the size of brain lesions, minimizes inflammation, and induces neurogenesis.

The testing of low-level laser therapy was conducted on rodent models at intervals of one treatment or three treatments per day.  Neurological functionality improved significantly for the laser-treated rodents compared to an untreated control group.  This improvement occurred within 2 weeks and was characterized by significant increases in synaptogenesis as a result of synapsin-1 upregulation.

The laser treatment simultaneously increased BDNF (brain-derived neurotrophic factor), another important component of mental health.  Despite the fact that this study was conducted on rodent models, the effects were significant.  It could be speculated that similar synaptogenesis effects may occur with low-level laser therapy (LLLT) in humans.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25196192

8. Increase BDNF Levels

If you want to optimize your brain’s ability to form new synapses, you may want to learn how to increase BDNF levels.  BDNF is an acronym for “brain-derived neurotrophic factor,” an important neurotrophin that aids in the formation of developing synapses.  Without sufficient levels of BDNF, synaptogenesis may be less likely to occur or may be suboptimal.

BDNF is responsible for helping your brain form both excitatory and inhibitory synapses.  When BDNF production is low, synapses are weakened.  When BDNF production is high, existing synapses are strengthened via long-term potentiation.  Despite the fact that this data is derived from rat studies, similar results are likely in humans; BDNF is known to be important for neurocognitive function.

  • Source: http://www.springer.com/us/book/9780387325606
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23534605

9. Various Proteins

The production of endogenous proteins can help promote formation of new synapses.  Proteins that have been documented as promoters of synaptogenesis include: Netrin, Osteopontin, and Thrombospondin.

Netrin: This is a protein that is thought to aid in the formation of neural circuits in the forebrain of mammals, especially during periods of peak synapse formation.  Researchers have demonstrated that “Netrin-1” is able to promote synaptogenesis within the cortical neurons of rats and mice.  Specifically, Netrin-1 increases the quantity and strength of excitatory synapses between cortical neurons.

Osteopontin: This is a protein molecule that has been found to improve synapse reorganization and recovery following traumatic brain injury (TBI).  It is believed to promote synaptogenesis via its action on synaptin-1.

Thrombospondin: This is a protein that is secreted from glial cells and promotes synaptogenesis while simultaneous maintaining synapse stability.  It is also thought to aid in the remodeling of synapses following brain injury and/or exposure to various drugs.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25624796
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25151457
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24174661

Benefits of Synaptogenesis

There are many benefits associated with synaptogenesis, including cognitive enhancement and flexibility.  Adults with lower levels of synapses often experience reductions in cognitive function compared to those with an increased number of synapses.  More synapses may also reduce the likelihood of neurodegeneration.

  • Cognitive enhancement: If you want to ensure that your brain develops to the best of its capability, increasing the potential of synaptogenesis may be a good start.  Intellectual impairment and cognitive deficits are associated with reductions in the formation of synapses.  To enhance your cognitive function, it may be smart to engage in activities that promote synaptogenesis.
  • Delay / prevention of neurodegeneration: There is evidence linking neurodegenerative diseases with synaptic deficits.  Those with diseases like Alzheimer’s tend to have less synapses and are thought to benefit from the process of synaptogenesis.  Various phosphatide precursors are being engineered specifically to induce synaptogenesis among those with Alzheimer’s disease.
  • Learning: The act of learning, especially motor skills are associated with synaptogenesis.  When you learn something new such as how to ride a bike, your brain forms new synapses.  These synapses are produced via synaptogenesis and are strengthened with future usage.  This is why eventually you can ride your bike without falling off.
  • Memory formation: Synaptogenesis is thought to aid in memory formation.  Those with impaired memory function may have a reduction in the number of cortical synapses.  Processes that promote synaptogenesis may bolster the strength of new memories.
  • Mood boost: Those with depression are thought to have impaired synaptogenesis.  By forming new synapses, you may be able to alleviate certain depressive symptoms and ultimately feel happier.  While mood improvement may not occur solely as a result of forming new synapses, some researchers hypothesize that it does.
  • Neuroplasticity: Synaptogenesis will allow your brain to adapt to various stimuli via neuroplasticity or self-directed neuroplasticity.  With a greater number of overall connections, you’ll have an easier time adapting to novel experiences.  Furthermore, with new experiences, your brain forms connections to help you function in related future situations.
  • Stress reduction: There is evidence that stress may impair your brain’s ability to form new synapses or at least new connections in regions associated with higher-order thinking like the prefrontal cortex.  Significant stress bolsters activation of the amygdala or “fear-center” and may be detrimental to preexisting, healthy synapses.

Source: http://www.ncbi.nlm.nih.gov/pubmed/25107590

Things That May Impair Synaptogenesis…

There are several things that may impair your brain’s ability to form new synapses.  There hasn’t been extensive research conducted with the specific intention of determining synaptogenesis disruptors.  That said, to be on the safe side, you may want to avoid things that kill brain cells in addition to the stuff listed below.

Anesthesia: It is recommended to avoid anesthesia at all costs if you want to retain your existing synapses and/or actively form new ones.  Researchers note that general anesthetics disrupt the balance of neurotransmitters and homeostasis necessary for neuronal signaling.  This results in a cascade effect throughout the brain, leading to impairments in formation of developing synapses and inhibition of synaptogenesis.  Just one exposure to anesthetics could result in permanent impairment in formation of certain synapses.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22762476

BPA (Bisphenol A): The synthetic xenoestrogen, BPA (bisphenol A) is present in many plastics.  Exposure to bisphenol A in rodents has been shown to reduce hormone levels and ultimately inhibit the process of synaptogenesis.  It specifically impairs synaptogenesis in the medial prefrontal cortex (mPFC) of rodents.  It is not a stretch to think that BPA wouldn’t have similar harmful effects in human populations.  BPA exposure was also associated with a reduction in preexisting synapses in the brain – yet another reason to avoid plastics containing bisphenol A.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18048497

Excess stress: While some stress may be beneficial for learning and change, excess stress may damage synapses and prevent formation of synapses in areas that promote optimal brain function and health.  It is best to practice stress reduction if you suspect that your high stress is interfering with your brain functioning.

Impoverished environment: Individuals growing up in an impoverished environment with few stimuli and a lack of enrichment may have fewer synapses than those in standard environments.  While those in an enriched environment may have up to 25% more synapses than individuals in a standard environment, the degree of synaptic deficit is unknown among those in an impoverished environment.

Suboptimal genetics: There is some research highlighting the fact that certain genetic polymorphisms are likely to impair synaptogenesis.  If you’ve inherited various genes that reduce your brain’s ability to form new synapses, this may result in cognitive deficits and learning disabilities.  For some individuals, inheriting the wrong genes can put them at a major disadvantage in regards to synapse formation.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22374772

Limitations in Synaptogenesis Research

There are some notable limitations in regards to synaptogenesis research.  Most evidence for synaptogenesis is derived from rodent studies, specifically involving rats.  It remains unclear as to whether human adults are able to form new synapses following synaptic pruning.

  • Lack of human studies: There are no documented human studies suggesting that synaptogenesis occurs during adulthood. While it is known that neuroplasticity and synaptic plasticity are maintained throughout adulthood, the degree to which new synapses form isn’t fully understood.
  • Unclear benefits: While it is thought that more synapses result in enhanced cognitive function, the degree of potential benefit is unclear.  It is certainly possible that by forming new synapses, the brain is able to recover from various mood disorders and cognitive deficits.
  • Location of synaptogenesis: The formation of new synapses can occur in various regions of the brain. Would the formation of new synapses in one region be preferred over formation of synapses in another?  For example, what if the amygdala began forming new synapses via synaptogenesis – would this strengthen the stress-response and/or anxiety-related behaviors?

Do you think synaptogenesis warrants further research?

Feel free to share a comment regarding whether synaptogenesis warrants further research.  Do you believe it should be studied more than neurogenesis, vice-versa, or that they should receive equal scientific attention?  It appears as though there are significant benefits associated with synaptogenesis, but it is unknown as to whether the synaptogenesis is responsible for these benefits or whether it is one of many complex functions that facilitates optimal brain health.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25458214

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{ 1 comment… add one }
  • danielle brown January 28, 2016, 1:16 am

    *Marvelous* article!! Thank you. (And, yes, of course, we really do need further research.)

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