Journal Review Episode #7

Journal Review | Episode #15 – Myasthenia Gravis 31:57
Journal Review | Episode #14 – The Benefits of Low-Level Laser Therapy (Photobiomodulation) for General and Athletic Populations 28:46
Journal Review | Episode #13 – Saint John's Wort 14:49
Journal Review | Episode #12 – Plastic Pollution: The Effect of Micro and Nano Plastics on the Human Body 30:54
Journal Review | Episode #11 – Anti-Obesity and Other benefits of Gynostemma Pentaphyllum 34:06

This episode of journal review will focus on the neurotransmitter GABA.

GABA – decreases(blocks/inhibits) brain activity in nervous system. Calming effect. It is popular supplement, bc the only naturally occurring foods containing it are fermented ones like kimchi, miso and tempeh. GABA is often taken to treat illnesses such as seizure disorders, movement disorders such as Parkinson’s disease, ADHD, anxiety, panic disorder, mood disorders (like depression), also, GABA containing supplements have been shown to work great in cases of hypertension. https://www.healthline.com/health/best-brain-boosting-products#5

GABA – non-protein amino acid, inhibitory neurotransmitter. (Amino acid neurotransmitter)
often synthesized by the amino acid glutamate via the enzyme glutamic acid decarboxylase. Inhibitory neurotransmitters make a neuron less likely to fire, an excitatory neurotransmitter does the opposite. Glutamate is an example of an excitatory neurotransmitter that is counterbalanced by GABA. GABA is Responsible for most of the inhibitory effects on the mammalian brain, especially in the CNS. This inhibitory effect is often felt as a calming sensation in a mature brain (an interesting side note is that GABA is actually an excitatory molecule in a developing brain) GABA is known to improve sleeplessness, depression, enhancing immunity, relieve anxiety & menopause syndrome, blood pressure, obesity and visual cortical function.

Intro

GABA binds to GABA-A and GABA-B receptors, to modulate and block impulses between nerve cells. Imbalances in GABA can lead to anxiety disorders etc. GABA decreases the tendency of a neuron to generate an action potential.
GABA is released from a synaptic knob in vesicles that will bind to target cell’s gabaergic receptor. the Two types of GABA receptors are GABA A and GABA B. GABA A (ionotropic) receptors rapidly cause Cl channels of the neuron to open, Cl- rushes in, making the inside of the cell more negative and less likely to fire an AP [j1] , this is known as hyperpolarization. GABA B receptors (Metobotropic g-protein coupled receptors) (commonly stimulated by the drug baclofen) also result in hyperpolarization – when GABA B receptors are activated, K+ ions to flow out of neuron and cause the neuron to be more negative. GABA B receptors also have presynaptic Ca2+ channelinhibition ability which can prevent a neuron from firing. However, GABA B receptors are a slower, delayed way of signaling, the signal can also last much longer than GABA A receptors, (up to hundreds of milliseconds). The result is an inhibitory post synaptic potential (IPSP). Because of this, and possibly that GABA receptors are found commonly in the CNS, GABA is known to have calming effect in the brain. https://www.verywellhealth.com/gaba-5095143#citation-1

Subunit variation and effect on GABA response.

When GABA is released, it is quick to saturate and activate the receptors, its concentration declines very quickly to, but it is slower to unbind from the receptor causing the (electrical) current generated in the target neuron to last longer. The 5 protein subunits making up a GABA receptor (2B, 2A and one gamma) will determine how long the current lasts (5-100s of milliseconds). The length of the current will determine your Brain rythms.
In order to grasp part of the significance of GABA it is important to provide a refresher on brain waves. Gamma brain waves have the highest brain wave frequency of 27Hz or more, and are associated with memory processing, formation of ideas, language and various types of learning. Beta brain waves have a frequency of 12-27 Hz, these brain waves are largely present during times of stress, anxiety, fight or flight stimulation. Alpha brain waves have a frequency of 8-12 Hz and are present in drowsiness, meditation, presleep, prewake, and the initial stages of an unconscious mind, as well as durng a runner high. Theta brain waves have a frequency of 3-8 Hz and are present while dreaming or REM sleep. Finally, Delta brain waves have a frequency of 0.1-3 Hz and are present during deep sleep, also during this time Human growth hormone, anti-aging hormones like melatonin and DHEA are released. https://curejoy.com/content/different-types-brain-waves/
(The rate at which GABA unbinds from receptor determines synaptic current in the neuron, and this is determined by the subunit structure.) So, depending on the subunits comprising a given receptor, synaptic currents can last from 5 to 10 ms to hundreds of milliseconds. This variability in duration seems to be important in memory formation, directed attention, and processing of sensory stimulation (determining neuronal network synchronization.) For example, fast phasic [j2] inhibition caused by a GABA release tends to create fast brain rhythms (such as gamma waves in hippocampus and cortex; Klausberger et al., 2002, 2004), whereas slow inhibition/ GABA release produces slow brain rhythms ( such as delta in renticular nucleus;
During gene expression, complex epigenetic regulation can occur, certain nucleotide base pairs in the DNA or RNA can be disrupted, or DNA packaging around substances called histones can experience interference which can affect which areas of the DNA are being expressed. Processes such as DNA methylation can also affect the expression of genes. These epigenetic regulations result in many different amounts of each type of GABA subunit.
In order to have an optimally functioning brain, a balance between fast and slow brain waves is needed, and this depends on the GABA subunits. (“In effect, maintaining balance between fast and slow synaptic currents (brain waves, theta, gamma etc.) might be facilitated by having the expression of one subunit with a particular physiological characteristic being balanced by the concurrent expression of another that acts in opposition to the first.”)
Having the right balance of receptor subunits (either fast or slow) is important to Synaptic timing patterns which control the rhythms within a brain area. Coordination between the subunits is essential for appropriate neural activity.
Interestingly, when the brain synchrony is altered, neurological disorders, sleep disorders and epilepsy can be experienced. Epilepsy is a central nervous system (neurological) disorder in which brain activity becomes abnormal, causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness
Coordination between subunits(?) advantageous for appropriate neural activity, organization (?) is tied to stressor reactivity, and is altered by acute and chonic stressor activity. Epigenetic regulation – sometimes G-C pairing can be disrupted… cytosine can be methylated by (one of 3 types of) DNA methyl transferases. The methylation of C attracts histones to wind and condense the DNA, Histones can either https://pubs.niaaa.nih.gov/publications/arh21-2/127.pdf

Looking at how GABA can be cultivated and produced efficiently.

Recently, due to the spike in demand for GABA, methods have to be created in order to optimize the production of this molecule. https://www.mdpi.com/1422-0067/21/3/995/htm

The enzyme Glutamic acid decarboxylase (GAD) (that we covered earlier) is widely present in microorganisms, plants and animals. Microorganisms such as yeast, fungus and bacteria can be great sources of GABA because their production of the molecule is easy to control. The enzyme GAD is also found in strains of Lactic Acid Bacteria (LAB). These microorganisms can be isolated from traditional fermented foods such as cheese, yogurt, kimchi, paocai and others. Fermented foods rich in L-glutamate such as cheese, are great sources for GABA producing LAB. Researchers have found that most LAB, GAD activity is optimized around a pH of 4-5, and a temperature of 30-60 C. However, finding the right environment for each individual strain to reach optimum GABA production is very complicated. In addition to optimizing fermenting conditions, scientists can also create higher-yield strains via breeding, genetic manipulation and other tactics. It is also essential to have enough L-glutamate (precursor) present.

Ways to increase your GABA endogenously via diet

To get the effects and benefits of GABA, supplements may help but are not necessary.
Glutamate (excitatory neurotransmitter, Needed to make GABA

Glucose → Glutamate (neurotransmitter) → glutamine (non-neurotransmitter AA) →neurons (so no effect as it is transported before being made into GABA).

Glucose → glutamate B vitamins (B1 – thiamin, B2 – riboflavin B3 – niacin, B5 – pantothenic acid. are essential for glucose converted into glutamate. Also requires lipoic acid, and vitamin B6.
- Liver is very high in B vitamins, and also lipoic acid. Lipoic acid is also found in kidney and heart. Nutritional yeast, whole grains and legumes are great sources for most B vitamins.
- Note; cooking destroys vitamin B6 bioavailability, certain raw foods such as bananas are great sources of B6.
Glutamate →glutamine
- Needed magnesium
- and ATP (need B vitamins and Biotin, minerals, good thyroid and insulin status) diabetes, thyroid issue etc. could mess with your ability to create GABA.
Glutamine → GABA

Uses vitamin B6. Salt and potassium (fruit & vegetables are good for this with a low fat diet.) are necessary for GABA to function properly.

Excess GABA often relsutls in hypotension, nausea, constipation decreased apetite, fatigue, muscle weakness. This is generally an excessive slowing of the body, and as one might expect, caffeine or nicotine are able to counteract excess GABA.

On the flip side, too little GABA can result in anxiety depression concentration and memory problems, muscle pain/headaches, insomnia and sleep problems, epilepsy, chronic pain and inflammation, hypertension and even alcoholism.

Anxiety, MDD [j3] and mental illness.

While serotonin, cytokines, BDNF, CTRH, various interleukins and other peptides could very well contribute to mental illness, we will focus on how GABA can ~~effect~~affect mental illness and what can cause a GABA imbalance. What can influence GABA receptor functioning (which can lead to imbalances.)? perturbations or alterations to the normal (in this specific case its) GABA-A receptors can cause alterations in neural activity. it is likely that altered GABA-A receptors could be partially responsible for mood disorders. Disturbances in the enzymes used to produce GABA, such as glutamic acid decarboxylase (GAD), could accompany MDD.
Studies have shown GABA to be heavily linked (along with epinephrine and serotonin) to depression, anxiety. (research has found that “(a) GABA levels in plasma and in CSF were increased in stress situations, (b) stressors influenced GABAA receptor functioning, (c) treatments that increase vulnerability to elevated anxiety and depression-like behaviors, such as early life stressors, also influence GABAA subunit expression, and (d) drugs that affect GABAA activity are effective in attenuating anxiety”) “In particular, it was reported that depression was accompanied by lower levels of GABA in cerebrospinal fluid. it was reported that GABA levels within the PFC were inversely related to severity of depression and GABAA receptor subunit expression was likely altered in depressed suicides” apparently, the mRNA expression of GABAa subunits are either up or down regulated (more or less of them) in patients with MDD. https://www.ncbi.nlm.nih.gov/books/NBK107210/
Another study found that levels of GABA and N-acetylaspartate in the occipital region of the brain and were significantly lower in recovered depressed and bipolar subjects than in healthy controls, while glutamate & glutamine conc. Was higher. https://pubmed.ncbi.nlm.nih.gov/17210135/
– when mRNA gets translated into amino acids, certain sections of the gene could be up or down-regulated which would cause MDD. In this specific study, the GABA-A (a1) and GABA-A (b3) subunits of GABA-A receptors in the cortical areas were upregulated. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257393/ These subunits are created differently. In one specific study, the variation in frontopolar cortex (FPC) of depressed suicides effected mRNA expression. the mRNA expression of certain subunits, (the α₁, α₃, α₄, and δ) was lower (less expression) in depressed suicides than in controls. (as was the expression of CRH Type 1 receptors; the latter was coupled with elevated levels of the peptide itself and thus may have reflected a compensatory down-regulation”)

Miscellaneous studies on GABA working within the body.

The purpose of the following studies are to show the vast impact that GABA has on many aspects of the body.

https://www.sciencedirect.com/science/article/abs/pii/S138824572100064X

a study looked at the The anti-obesity and anti-diabetic effects of γ-aminobutyric acid (GABA) in mice. This study concluded that when mice received 5g of GABA for every Kg of their regular diet, food intake was decreased by 30%, fat accumulation and body-weight gain was decreased. Glucose metabolism was improved. These changes suggest that 5% GABA intake possibly induces calorie restriction. Interestingly, a combination of low-dose dietary GABA (0.5% and 2%) and vigabatrin (inhibitor of GABA transaminase (GABA-T)) markedly increased the levels of circulating GABA and strongly exerted antiobesity-like effects. Brain GABA levels increased slightly upon 5% GABA intake, but significantly upon intake of the low-dose GABA–vigabatrin combination. Even though we must remember this is an animal study, it is interesting to consider that the manipulation of peripheral and brain GABA metabolism by targeting GABA-T may lead to the development of novel interventions for overeating and obesity.
A study including mice with acute liver failure (ALF) from liver injury and associated with high mortality found that mice treated with GABA experienced an attenuation of hepatocellular necrosis, increased mitochondrial integrity and a reduction in apoptotic proteins. All of these factors prolonged survival in mice with ALF, this study suggests that GABA protects against ALF in mice.
Another study looked how GABA was able to reduce inflammation in beta-cells in the pancreases (responsible for releasing insulin.) GABA also had regenerative effects on pancreatic beta cells, GABA also can induce alpha, glucagon-producing cells to change into beta, insulin producing cells. GABA can be seen as a potential therapy for type- 1 diabetes.
A meta-analysis of 40 studies found that patients with autism spectrum disorder and depression had lower levels of GABA in their brain that controls.
A study found that in pts with secondary progressive MS (relapse from MS, irreversible, continuous nerve decline) performed worse that controls in all physical, motor, verbal, memory, processing speed tests. These pts also had lower GABA levels. In this study, reduced motor f(X) in the right upper and lower extremities was associated with a decrease in GABA. There was also a predicted decrease in grip strength of the pts. The results of this study lead these researchers to consider that low GABA may contribute to the neurodegenerative process. It is thought that GABA modulation for MS has potential.
In the agricultural area, GABA was found to be successful in stopping salt-stress in plants such as maize and tomatoes as well as other plants. GABA alleviated membrane damage and oxidative damage. Salt stress inhibits plant function and photosynthesis. This study suggests that GABA improves photosynthesis and inhibits oxidative stress in plants with salt stress.
A study showed that the often-helpful GABA exacerbated inflammation in pts with ulcerative colitis, inhibited colonic epithelial cell proliferation and increased apoptosis in that region. Although there may be a great amount of positive studies about GABA it is necessary to acknowledge every aspect of a topic.

These were just a few studies to show how much of an impact the molecule GABA has on living organisms.

https://www.ncbi.nlm.nih.gov/books/NBK107210/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257393/

https://www.webmd.com/vitamins-and-supplements/gaba-uses-and-risks

https://www.verywellhealth.com/gaba-5095143#citation-1

https://www.sciencedirect.com/science/article/pii/S1756464621000165 – (anti- obesity in lean mice)

https://www.sciencedirect.com/science/article/abs/pii/S138824572100064X – (GABA & ADHD)