GABA/Glutamate Balance Part 2

Uncovering root causes and what you can do about it

This article serves as a follow up to my most recent post, “ GABA/Glutamate Balance Part 1”. If you haven't read that yet, I recommend it because it is going to add a lot of context to everything we discuss below and saves me from having to explain the basics of E/I balance again. It's linked here, and is available for free to everyone.

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Balance between GABA and glutamate is required to have a healthy, well functioning brain. The relationship between these two molecules—the primary inhibitory and excitatory neurotransmitters—influences the function of every single neural circuit in the brain. It’s not a coincidence that an imbalance of the two is a feature in many neuropsychiatric disorders (epilepsy, depression, OCD, Alzheimer’s, Autism, Schizophrenia, etc).

However, an imbalance doesn't always result in a psychiatric condition. Even a relatively minor GABA/glutamate (E/I) imbalance can cause general cognitive impairment. Some of these symptoms may include:

• Anxiety

• Inability to focus

• Social deficits

• Brain fog

• Irritability

• Sensory hypersensitivity

• Insomnia

• Racing and intrusive thoughts

In this context, these symptoms can be chalked up to one of two things; too much glutamate signaling or not enough GABA signaling (or a combination of both). Unfortunately, a state like this often involves a feedback loop in which excess glutamate can damage neurons, negatively impacting GABA signaling and increasing glutamate signaling further, worsening the imbalance. Therefore, to truly fix an imbalance you need to address the root cause and fix the problem at the source to stop the feedback loop.

Schematic summary of different aspects of excitotoxicity (excess glutamate induced damage), including the main cellular defenses against it, the main causes, the players involved in its mechanisms, and general cellular consequences. [Image Source]

While that seems relatively simple, there’s one glaring issue; the root cause could be one of several factors, many of which overlap with and contribute to one another. As a result, what it takes to fix an imbalance is going to be highly individual and, as we’ll get into shortly, your current state of health.

I want to preface the rest of this article by saying that this is not a “How to guide” and will not provide step by step instructions on how to fix an imbalance because 1) I am not your doctor, and 2) there is no one size fits all protocol for something like this. This will take some effort on your part as an individual. You need to take a realistic look at the factors in your life that may be driving an imbalance, and do what you can to correct it.

I do not have all of the answers here (if I did this article would be hundreds of pages long), but I will do my best to explain the most common root causes and a loose framework for how you can start working to fix them through the implementation of supplements and lifestyle changes.

With that out of the way, let’s get into it.

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The more research I did for this article, the more I realized that E/I balance is a marker of good health. Many of the factors that have a negative influence on E/I balance are rooted in the pillars of physical health; circadian rhythm, light, diet, sleep, exercise, and mental health—meaning that for many, an imbalance is a symptom of other bodily dysfunction (unless of genetic or developmental trauma origin). 

Note: For the sake of brevity, I’m going to avoid diving into the weeds for each root cause and potentially beneficial intervention/supplement. I think it would hurt the reading experience and impair the accessibility of the information below to have it presented as a wall of text. If there is any specific topic you'd like to see a more in depth dive on, let me know in the comments. 

I've identified what I believe to be the main factors that may contribute to an E/I imbalance and subsequent cognitive dysfunction. They are as follows:

• Diet

  • Dietary requirement of metabolic cofactors (B vitamins, magnesium, etc.)

  • Obesity and metabolic syndrome (insulin resistance, high blood pressure, etc.) increase oxidative stress and induce neuroinflammation

  • Gut health

    • Gut-brain-axis

    • Gut inflammation = neuroinflammation

• Circadian Rhythm

  • Importance of sleep

    • E/I balance shifted toward excitation with sleep loss

    • Glymphatic clearance is enhanced during sleep (clearance of glutamate and waste)

    • Sleep loss induces neuroinflammation

  • Cell specific circadian rhythms for interneurons and other cell types influencing their activity

  • Circadian rhythm influences EVERYTHING

• Chronic Stress

  • Chronically elevated cortisol increases glutamate and downregulates GABA via HPA

  • Induces neuroinflammation and increases BBB permeability

  • Reduces BDNF

  • Induces atrophy of dendrites in cortex and hippocampus

• Metabolism and Mitochondrial Health

  • GABA-Glutamate-Glutamine cycle is dependent on mitochondrial metabolism

  • Glutamate uptake and recycling is metabolically expensive

  • ATP production important for all cells to function properly (especially PV interneurons, key regulators of E/I balance)

  • Excess reactive oxygen species and nitric oxide induce inflammation, increase BBB permeability, and impair mitochondrial ATP production

• Inflammation

  • Peripheral inflammation can induce neuroinflammation

    • E.g. gut, exposure to irritants, etc.

    • Influx of inflammatory cytokines and potential breakdown of BBB, which allows dietary free glutamate and other potentially harmful molecules into the brain

  • Reduces BDNF

  • Increases glutamate release

  • Microglia activation

  • Positive feedback loop of more inflammation

  • Glymphatic clearance dysfunction induced by neuroinflammation

  • Increased oxidative stress

• Non-Native Electromagnetic Frequencies (nnEMF)

  • Increases calcium influx (mitochondrial damage and increases ROS)

  • Increases permeability of BBB

  • Increases glutamate release

  • Impairs synaptic plasticity

• 5-AR and DHT derived neurosteroids

  • DHT derived steroid molecules are highly GABAergic

• Childhood Trauma and Genetic Factors

  • Traumatic stressors in childhood and genetic factors can alter the developmental trajectory of the brain and E/I balance

• Feedback loop of excess glutamate → mitochondrial damage and oxidative stress → more glutamate release

Okay, that’s a lot to take in… Now let's look at how to potentially combat these issues.