Understanding GABA/Glutamate Balance
Including 3 supplements you can use to maintain balance
When most people think of neurotransmitters, they think of the more popular “neuromodulators”: dopamine, serotonin, and even acetylcholine. But in reality, GABA and glutamate are the ones running the show. They are the most important neurotransmitters in the brain by far. In fact, ~90% of all synapses in the brain release glutamate, and glutamate neurotransmission accounts for 80% of the brain's energy usage [source].
Because of its overwhelming predominance as the brain’s primary messenger molecule, glutamate needs something to keep its activity in check and prevent excessive signaling. That something is GABA. See, GABA and glutamate are direct opposites in the way they function. Glutamate is the primary excitatory molecule in the brain and it drives other neurons to fire as a way of transmitting information. On the other hand, GABA is the primary inhibitory molecule, and it stops neurons from firing as a way of controlling neuronal activity. Both are transmitting information via receptors located on other neurons, but one induces more neuronal activity while the other inhibits it. As a result, a balance between these two molecules is necessary to ensure that the glutamate signaling does not occur in excess.
This relationship shapes the way the brain and its neural circuits function, and any disruptions in this balance can impair cognitive function, which is why we see GABA/Glutamate balance as a common feature in neuropsychiatric disorders [Examples: Autism and Schizophrenia, Alzheimer’s, ADHD, Depression, OCD].
GABA/Glutamate balance is commonly referred to as Excitatory/Inhibitory (E/I) balance in the scientific literature, referring to the excitatory and inhibitory nature of glutamate and GABA, respectively. For the sake of brevity, I will refer to it as E/I balance for the remainder of this article.
The concept of E/I balance throughout the entire brain is very complex, because it involves many brain regions with different types of neurons. For that reason, let’s focus in on the cerebral cortex, a structure that is heavily reliant on E/I balance to function properly. The cortex is the outermost, “lumpy” layer of the brain and is responsible for the more complex cognitive functions, such as thinking, planning, focusing, and socialization. It is made up entirely of glutamatergic and GABAergic neurons, which are organized into six layers.
About 75% of all cortical neurons are glutamatergic pyramidal neurons (release glutamate), and the other 25% are GABAergic interneurons (release GABA) [source]. As a result, all higher order cognitive processes (as mentioned above) revolve around these two neurotransmitters.
Other neurotransmitter systems provide input to cortical neurons via long-range projections, so they do have an impact on GABA and glutamate neurotransmission. However, all cells located in the cortex only release either glutamate or GABA.
Pyramidal neurons receive input from a wide variety of neurons, both long-range and local, and release glutamate on to other neurons as a means of transferring information. All the while, the small population of interneurons release GABA onto local pyramidal neurons to inhibit their activity and effectively control their output.
You can think of E/I balance in terms of a signal to noise ratio. In such analogy, signal refers to meaningful input or things in your environment worth paying attention to, and noise refers to input that is not meaningful. With too much neuronal activity, the noise in a circuit increases and it becomes more difficult for your brain, and the neural circuits within it, to respond to meaningful inputs.
For example, with too little GABA transmission in relation to glutamate, pyramidal neuron activity increases. As a result, neural circuits can become “noisy” due to excess firing, which makes complex computations much harder. This directly interferes with the functions that the cortex is responsible for and has been shown time and time again in animal studies– although many focus on social behavior or disease-specific deficits [Example: Social deficits and information processing].
The opposite type of imbalance can be true as well, where GABA activity outweighs that of glutamate and you may become tired, unable to focus, and less likely to form memories. This is actually the state we want to be in when trying to fall asleep, which is why many useful sleep supplements work by elevating GABA activity or inhibiting glutamate.
The Importance of Interneurons for Maintaining E/I Balance
The importance of interneuron function cannot be overstated when it comes to a well-functioning cortex (and brain). The study of interneurons and their specific subtypes has been an important topic in neuroscience research since it has become apparent that they play a necessary role in regulating neuronal activity and, therefore, complex cognitive processes.
In the cortex, E/I balance is essentially reliant on this small population of neurons, since they’re the main source of GABA. Any disruption in their function–even minor–can impair cortical function to a significant extent and may even be the root of certain symptoms in neuropsychiatric disorders [source].
This is especially true of the parvalbumin (PV) interneuron, an interneuron subtype of specific interest to researchers because they can fire incredibly fast, attach directly to the cell bodies of pyramidal neurons, and inhibit a large number of pyramidal cells with large axonal arbors. Not only are these interneurons firing incredibly fast, releasing tons of GABA on to nearby pyramidal cells, their area of effect is super close to the axon, which makes them more impactful at inhibiting action potentials compared to other subtypes that focus on inhibiting the dendrites. This offers them an immense amount of control over pyramidal cell activity, which prevents unnecessary spiking, decreases pyramidal cell firing, and, as a result, contributes significantly to E/I balance.
Furthermore, these interneurons tend to work in ensembles, or small networks of cells that fire simultaneously. Since each individual PV interneuron can effectively inhibit a large number of pyramidal neurons, a single ensemble can coordinate the activity of an entire cortical microcircuit.
The fast-spiking phenotype of PV neurons is a double-edged sword though. While they can inhibit pyramidal cells extremely well and push extremely precise spike timing on them, their ability to spike fast leaves them vulnerable to any metabolic deficits [source]. These cells have monstrous energy requirements to frequently recover from action potentials, continually package and release GABA, and filter glutamatergic input from other neurons, which means that any disruption in their mitochondrial function or energy production can interfere with local inhibition, leading to an E/I imbalance.
Metabolic deficits can interfere with E/I balance in other ways as well since GABA and glutamate synthesis, neurotransmitter release, recovery from action potentials, and many other factors are all dependent on metabolism and ATP production. This is something I will write about in much greater detail in the near future.
Potential Symptoms of an E/I Imbalance
Just because E/I imbalance is a common feature in neuropsychiatric conditions, obviously doesn't mean that E/I imbalance = neuropsychiatric condition. However, the sentiment that an E/I imbalance can lead to some type of cognitive impairment is undeniably true.
Some potential symptoms of a relatively minor E/I imbalance include:
Anxiety
Inability to focus
Social deficits
Brain fog
Irritability
Sensory hypersensitivity
Insomnia
Racing thoughts
Intrusive thoughts
I say “relatively minor” here because extreme imbalances are often accompanied by seizures and neuronal death as a result of excitotoxicity (calcium overload due to excess glutamate).
One of the easiest ways to test if you have an minor E/I imbalance is to take a small to moderate dose of L-Theanine (a glutamate antagonist). If it rids you of these symptoms and improves cognition, then you're likely dealing with an imbalance.
A decent proof of this concept is the synergy behind caffeine and L-Theanine. As a stimulant, caffeine increases neuronal activity which shifts the E/I balance towards E (increasing glutamate). Theanine counteracts this by antagonizing glutamate receptors, which helps restore balance and smooths out the caffeine stimulation to produce a calm focus that this stack is famous for.
Long-term E/I imbalances are detrimental to brain health as well. Excess glutamate signaling–as a result of reduced GABA or otherwise–can overactivate the NMDA glutamate receptor, which is involved in learning and synaptic plasticity. Overactivation of this receptor leads to excessive calcium entering neurons, which has a negative effect on mitochondrial health and can damage neurons through production of reactive oxygen species. If bad enough, this cascade can even lead to cell death (aka excitotoxicity), but it doesnt need to go that far to be detrimental.
Even further, calcium overload can contribute to a feedback loop of excess glutamate.
Excess calcium → Negative impact on mitochondrial health → Less energy production → Impaired interneuron function or hyperexcitability of pyramidal cells → Increased glutamate release → Even more calcium influx and more glutamate release
Supplements to Combat an E/I Imbalance
There are three supplements that stand out among the rest to rest to fight an E/I imbalance, including:
Magnesium
L-Theanine
Taurine
Homage Grimhood (@grimhood on X). Grim is a friend of mine, and has been posting about these three supplements for their effects on GABA and glutamate for years.
These supplements are easy recommendations because they are cheap, effective, and safe for daily use. All three have either an inhibitory effect on glutamate, are pro-GABA, or a combination of both.
Here’s a quick rundown on why they're so effective…
Magnesium
First off, most people don't consume enough magnesium [source], so it's a great thing to supplement for most people.
Most notably, magnesium is an NMDA receptor channel blocker. This directly protects your neurons from excessive calcium influx and allows these receptors to function as intended. NMDA receptor blockade is a key function of magnesium in the brain, and is the main reason people experience an anti-anxiety effect when they start supplementing with it. I’ve written more about this interaction in this article for those who are interested.
Furthermore, magnesium is an essential cofactor for thousands of reactions in the brain and body. So many that I’m not even going to attempt to list all of its functions, but here's a great figure illustrating many of them;
Of note for its positive impact on E/I imbalance, we have:
Inhibits NMDA receptor
GABAA receptor agonist
Essential for ATP synthesis and utilization
Decreases glutamate release
Inhibits calcium channels
Inhibits oxidative stress and inflammation
Cofactor for carbohydrate metabolism enzymes
In short, take your magnesium. It’s anti-glutamate and pro-GABA, making it the most effective supplement for fighting an E/I imbalance.
Use multiple forms if possible, take at several points throughout the day, consume 5-10mg/lb of bodyweight in elemental magnesium, and increase your intake when using stimulants or are under excessive stress.
L-Theanine
Theanine is an amino acid that occurs naturally in green tea. It primarily functions as a glutamate antagonist, binding to glutamate receptors and reducing glutamate’s binding to them. This directly reduces glutamate activity and offers an insane synergy with magnesium to indirectly reduce NMDA receptor activity by inhibiting AMPA receptors.
It is safe, well tolerated, and can be dosed daily and multiple times throughout the day with no risk of tolerance [source]. It is another no brainer supplement for those looking to combat an E/I imbalance.
If you want to use L-Theanine as a sleep supplement, I highly recommend pairing it with magnesium to counteract a potential paradoxical excitatory effect that can occur in some individuals.
Taurine
Taurine is another naturally occurring amino acid, but it acts as a GABA receptor agonist among other beneficial mechanisms.
Of those other mechanisms, taurine notably helps maintain low levels of calcium in cells and plays an important role in energy metabolism, which further contributes to its neuroprotective and E/I balance promoting effects.
Conclusion
By now, it should be clear that maintaining E/I balance is crucial to having both a cortex and brain that are operating to the best of their ability. An imbalance may very well be at the root of some cognitive dysfunction, including symptoms mentioned above, because the brain relies on GABA and glutamate as their main neurotransmitters.
Stay tuned for an upcoming post on how to fix a potential imbalance. It’s too complicated to cover in a post like this because the root cause could be many different things, although the three supplements discussed above can be of great help for many and may even be enough to maintain a balance for some (especially magnesium due to its effects on the NMDA receptor and energy metabolism).
That’s all for now. Thanks for reading and feel free to leave any questions you have below,
-BowTiedNeuron
Disclaimer
This article is for education purposes only. BowTiedNeuron is not a doctor, and the contents of this article is not medical advice. Always consult your doctor before starting any new supplements.