GABA: Genetic variants that impact this inhibitory neurotransmitter

GABA (gamma-Aminobuyteric acid) is a neurotransmitter that acts to block or inhibit a neuron from firing. It is an essential way that the brain regulates impulses, and low GABA levels are linked with several conditions including anxiety and PTSD. This article explains the role of GABA in the brain - including how the neurons make GABA and the regulation of the amount of GABA inhibition. We will dive into the genetic variants that can alter your GABA levels and then finish with natural ways to increase GABA.

GABA: Creation, Transport, Reuptake, and Break down

Neurons are nerve cells that communicate with another nerve cell by sending an electrical signal along the axon to the next neuron. Ions moving in or out of the cell causes a change in the electron balance, resulting in an electrical signal. Excitation and firing: Neurons can be excited and send a signal (fire) due to a stimulus. For example, neurons in the auditory cortex of the brain respond to the noises that you hear. But just as important as it is for a neuron to be excited and transmit a signal, it is also important for there to be a way to slow down or turn of that firing when needed. Using noises as an example, you need to filter out the background sounds so that you aren't constantly bombarded.[ref] Putting on the breaks: Inhibiting or slowing down neurons is where the neurotransmitter GABA comes in.  About 20-25% of the neurons in the cortex of the brain are 'GABAnergic' neurons which release GABA to inhibit other neurons from firing. Here is a quick image of a neuron and the synaptic terminals so you can visualize what is going on with sending a signal. Keep in mind, though, the neurons can interact with more than one neuron - think of this looking more like an intertwined network rather than just one neuron signaling one other neuron.  (Creative Commons License)   Within that synaptic terminal at the end of the axon, the electrical signal causes the release of a neurotransmitter. Image of GABA release at the synaptic terminal of a GABAnergic inhibitory neuron.  

Ions flowing and neurons firing:

Neurons fire by building up an action potential. This is all done by moving ions (e.g. calcium, potassium, chlorine) into or out of the cell, causing a change in the polarization of the cell. Essentially: Polarization is when the electrical charge on the outside of the cell is positive and the inside of the cell is negative.  When the negative charge inside the cell reaches a certain voltage potential, the neuron 'fires', sending a signal down the axon to cause the release of a neurotransmitter into the synapse. One way to inhibit a neuron from firing is to move chlorine ions into the cell or potassium ions out of a cell, decreasing the action potential. This is what GABA does - it causes ions to move, changing the voltage potential within the cell. Web of interaction: Circling back to the image of neurons being like a net or a spider web, all interacting with each other. Some neurons may release GABA to inhibit another neuron from firing - while other nearby neurons could be sending an excitatory signal at the same time. It isn't an all or nothing deal, but instead is a complex system of moving electrons. Quick aside: GABA is not the only inhibitory neurotransmitter in the game. Glycine also works within the brain to inhibit excitation. Different parts of the brain have neurons inhibited by either glycine or GABA, thus focusing on just one or the other may not give you the results you are looking for.[ref] Recap: GABA is an inhibitory neurotransmitter that acts to decrease the stimulation of neurons.

Creation of GABA:

GABA is usually created from the amino acid glutamate using the enzyme glutamic acid decarboxylase (GAD). There are two different forms of glutamic acid decarboxylase, coded for by the GAD1 and GAD2 genes.[ref] A little background:  Glutamate is an amino acid that acts as an excitatory neurotransmitter, binding to its receptor and promotes activation of neurons. A lot of people think "MSG" and Chinese food when they hear the word glutamate, but glutamate occurs naturally throughout the body and is a vital neurotransmitter in the central nervous system. As an excitatory neurotransmitter, glutamate is imperative for learning, attention, and focus - but too much glutamate causes too much stimulation in the brain. Balance is needed between stimulation and inhibition. Where does the body get glutamate? Predominately from glucose. A precursor for glutamate called alpha-ketoglutarate is created in the mitochondria in the TCA  cycle (Kreb's cycle, producing ATP). The alpha-ketoglutarate then converts to glutamate, which can be used as an excitatory neurotransmitter.  Or, the glutamate can be further converted  -using the GAD1 enzyme and vitamin B6 - into GABA.[ref] Important point: The conversion of glutamate to GABA takes place in the GABAnergic neurons, which produce the GAD enzymes. Taking supplemental GABA likely does not cross the blood-brain barrier. Instead, GABA production occurs in the neurons where it is needed. Recap: GABA is created from glutamate using GAD1 or GAD2 enzyme with vitamin B6 as a cofactor.

Receptors for GABA:

When released from the neuron, GABA needs to bind to a receptor on another nearby neuron to send its signal. Without a receptor, there is no action from GABA. There are two well-researched GABA receptors: GABA-A and GABA-B
  • GABA-A receptors are ionotropic, Cl-  (chloride ion) channels  - allowing chloride to flow into a cell.  This quickly changes the polarization, and the receptors are found in quick-acting neurons.
  • GABA-B receptors are metabotropic, usually with potassium channels -- causing potassium to flow out of the cell.
The GABA-A receptors (GABRA family of genes) are the most abundant and present throughout the central nervous system (brain, spinal cord). GABA-B receptors (GABRAB1 gene) are more specialized. They work to limit the release of glutamate and also to autoregulate the amount of GABA. When GABA binds to the GABA-B receptor it is taken back into the neuron to be either recycled or broken down.[ref] A third GABA receptor (GABA - C) is thought to be important in circadian rhythm, sleep, and the retina.[ref][ref]

Breakdown of GABA:

You don't want too much GABA or too much glutamate at any one time. It's a balance. Eventually, GABA is removed from the system by converting into succinate - which is then used in the Krebs cycle in the mitochondria to make ATP.[ref] The enzyme succinic semialdehyde dehydrogenase (ALDH5A1 gene) is needed for the conversion of GABA into succinate.[ref] Rare genetic mutations in the ALDH5A1 gene cause succinic semialdehyde dehydrogenase deficiency, which decreases the breakdown of GABA. This results in increased brain levels of GABA. The increased amount GABA then downregulates the GABA receptors, such that the net effect is less of an inhibitory signal.[ref] GABA can also be metabolized into creatine, and an increase in both GABA and creatine are found in people with dysfunction in the ALDH5A1 gene.

GABA Transporter:

The removal of GABA from the synapse occurs from the GABA transporter called GAT1 (SLC6A1 gene). It allows for the reuptake of GABA in the synapse. GAT1 also clears GABA from the extracellular space. Animal studies show that knocking out the GAT1 gene causes spike-wave discharges in the brain, and people with rare GAT1 mutations can have epilepsy.[ref]

Drugs that affect GABA:

Increased GABA generally causes sedation. This can be accomplished through making the GABA-A receptors bind more quickly to GABA - or it can be through blocking the GABA-B receptors, thus leaving more GABA in the synaptic cleft.
  • The anesthesia propofol acts on the GABA system.[ref]
  • Benzodiazepines (e.g. Valium, Xanax, Klonopin) bind to GABA-A and cause it to bind more preferentially to GABA, thus increasing the inhibitory effects of GABA.
  • Phenibut blocks the GABA-B receptor, causing less GABA to be recycled and allowing more GABA to reach the GABA-A receptors (theoretically).[ref]
  • GHB is both a naturally occurring neurotransmitter (in small amounts) and a drug that has both legitimate and illegal uses. It has different effects on GABA at different levels. In general, GHB causes GABA levels to increase in the brain.[ref][ref]

Conditions linked to Altered GABA:

Anxiety disorders, PTSD:

As an inhibitory neurotransmitter, GABA puts the brakes on the release of neuropeptides in the brain that activate the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is what controls stress hormone release, such as cortisol from the adrenal glands. Some researchers think this interaction is a major player in anxiety disorders.[ref] Anxiety disorders such as panic attacks, PTSD, or generalized anxiety disorder are characterized by low GABA in certain regions of the brain.[ref] Additionally, people with an anxiety disorder may have overactivation in the amygdala, caused by low GABA.[ref] Not the whole story: Anxiety (and depression) are complex disorders with many variables involved, so while GABA may play a role, anxiety disorders are likely multifactorial for most people. People with post-traumatic stress disorder generally have lower brain GABA concentrations. Specifically, researchers found a reduction in GABA levels in the parieto-occipital cortex and the temporal cortex. Glutamate levels showed increases compared to control in the temporal cortex.[ref]

Major Depressive Disorder:

Recurrent depression is a huge problem, with an estimated 1 in 5 people in the US dealing with depression. For some people, dysregulation of GABA may be playing a causal role in depression. In conditions of chronic stress, a potassium-chloride transporter in the brain can be downregulated. This results in GABA being ineffective to inhibit the HPA axis, leading to depression for some people. Additionally, studies show that in acute psychological stress, GABA levels are decreased by 18% in the prefrontal cortex.[ref] Studies also show that patients diagnosed with major depressive disorder have lower levels of GABA in the cortex compared to healthy controls. Interestingly, glutamate levels were the same between the patients and the control group.[ref]

Epilepsy:

Too much excitation in neurons in certain regions of the brain can cause epilepsy or spastic disorders. Epilepsy is a complex topic, but essentially, an imbalance of GABA inhibition vs. excitation causes seizures. Many anticonvulsant drugs act by increasing GABA in the synapse.[ref] Genetic variants that decrease the function of the GABA-A receptors - essentially decreasing the GABA inhibition signal - show links to an increased risk of epileptic seizures.[ref]

Insomnia:

A study of brain GABA levels was conducted in people with primary insomnia who were not on medication. The results showed that people with long-term insomnia averaged 30% lower GABA levels in the brain than the normal sleeping control group.[ref] Medications that block the GABA-B receptors (thus altering the recycling of GABA) alter sleep patterns and decrease slow-wave sleep. Animal studies also show that GABA-A antagonists injected into the brain cause a significant increase in REM sleep.[ref][ref] Complex: It doesn't seem to be as simple as 'more GABA = better sleep'. Instead, it seems that drugs or supplements that act on GABA receptors may alter the structure of sleep (e.g. less slow-wave or more REM sleep).

Schizophrenia:

While there are still a lot of unknowns in schizophrenia, researchers theorize that this psychological disorder is due to a lack of GAD1 in certain regions of the brain.[ref] This lack of GAD1 theoretically leads to an imbalance of too much glutamate (excitation) and too little GABA (inhibition).

Autism:

Autism spectrum disorder is complex and heterogeneous. Some of the research on autism points to imbalanced glutamate and GABA neurotransmission.[ref][ref] One thing to keep in mind here is that GABA is an inhibitory neurotransmitter in the developed brain, but in the fetus or developing infant's brain, GABA acts in different ways. A recent study found that in adults with autism, one portion of the brain had statistically decreased levels of glutamate, with GABA being the same as controls.[ref]  Another study, though, found no differences in GABA or glutamate levels between young adults with autism and control in the brain regions examined.[ref]

High blood pressure:

Blood pressure control is a highly complex system in the body with many inputs.  Animal models show that spontaneous hypertension can be due to reduced GABA inhibition in the part of the hypothalamus that regulates blood pressure. The animal studies found significantly fewer GABAnergic neurons in the hypothalamus.[ref] Further animal research points directly to an increase in GABA-B receptors, which clear out GABA from the synapse and shift towards less GABA available.[ref] Injecting GABA directly into the central nervous system (animal studies again) reduces blood pressure.[ref]

Circadian Rhythm and GABA:

The area of the brain known as the suprachiasmatic nucleus (SCN) is where the body's core circadian clock is centered. The circadian clock plays essential roles in coordinating pretty much everything that goes on in the body - sleeping, waking, breaking down food, creating hormones at the right time, etc. The type of neurons in the SCN are primarily GABAnergic, with over 90% of the neurons expressing GABA. While GABA is primarily an inhibitory neurotransmitter, the exception may be in the suprachiasmatic nucleus where it seems that activation of the GABA-A receptor excites neurons. This is all dependent on the flow of different ions, and the SCN neurons have a different balance of ion transporters.[ref][ref][ref]  

GABA Genetic Variants:

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