Ansa Zakriya

Mary Jane Sasser

IRI/3/10h

April 24 2020

The Effect of Glutamate and GABA on Autism Spectrum Disorder

As of 2016 1 in 54 children are impacted by Autism Spectrum Disorder (ASD),

negatively affecting their neurocognitive functions, and making day to day responsibilities

onerous. Over the years autism has become more abundant, in 2000 1 in 150 people were

diagnosed with ASD, whereas in 2016 that number has almost tripled (CDC 2020). ​The etiology

of autism is linked to the imbalance of excitatory and inhibitory signals sent through the

neurotransmitters glutamate and gamma-amino butyric acid (GABA), leading to

maldevelopment of neurons.

Overall due to Autism being such a broad term there are many possible causes, which

leads to a spectrum of severity. ASD is characterized by poor social interaction, communication,

and repetitive behavior (Quaak 1). These behaviors have been associated with signaling errors.

Signals are sent through the brain by neurotransmitters, which work as messengers to direct the

signals. The neurotransmitter begins at the presynaptic terminal, the end of the neuron sending

the signal. That neurotransmitter is then released and enters the synaptic cleft, the region in

between the neurons. The messenger proceeds to bind to receptors on the post synaptic cell, the

neuron receiving the message which leads to a series of reactions. Excitatory signals increase the

chances that a neuron will fire an electrical signal, action potential, thus depolarizing the cell. On

the other hand inhibitory signals lower the actions potential, hyperpolarizing the cell. An action
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potential allows the information to be transferred from the post synaptic membrane down the

axon. The resting action potential when no signals are being sent is around -70 millivolt (mv).

Once the threshold is met, around -55mv, the action potential will be able to fire through the

entire neuron (Action Potential).

The major excitatory neurotransmitter is glutamate, while the major inhibitory

neurotransmitter is GABA; they work in unison to balance and determine what signals are passed

on. Excitation-Inhibition (E-I) is a result of “heightened inhibition from excessive parvalbumin

GABAergic inputs causing loss of excitatory glutamatergic synapses in mature mutant neurons”

(Kang 2). Decreases in the excitatory signaling pathway leads to a loss of E-I imbalance, such

loss means the threshold needed to fire an action potential will not be met. Cumulated evidence

has proven that the E-I imbalance leads to the etiology and symptomology of developmental

disorders. Glutamate and GABA work to maintain a balance between excitatory signals and

inhibitory signals; if there is an imbalance, then there will either be a lack or abundance of

signals. Varying amounts of each neurotransmitter are needed at different times. In order to fall

asleep and negate other signals there is more GABA at night, however, in the day when it is

necessary to react and think the GABA levels decrease while the glutamate levels increase. A

balanced amount of each neurotransmitter is necessary because this balance maintains the

organisms ability to function properly.

Genetics plays a crucial role in the etiology of ASD. Findings from twin studies suggest a

correlation between genetics and autism. These studies prove the importance of genetics through

the coordinance rate, the likelihood that a pair have the same traits. The coordinance rate among

male monozygotic twins for ASD is 77%, whereas dizygotic male twins have a coordinance rate
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of 33% (Quaak 1). Monozygotic refers to the offspring coming from one diploid cell being split

into two, in other words they are identical twins. Dizygotic means they are fraternal twins as the

offspring were produced from two separate eggs. The only difference between the monozygotic

twins and the dizygotic twins in terms of growth would be the DNA. Monozygotic twins share

the same set of DNA whereas the dizygotic twins inherited different sets. The monozygotic twins

have a higher coordinance rate which implies that the sharing of DNA relates to the root of the

disorder. The pair of twins inherited the same DNA, therefore they are more prone to developing

the disorder. Similar results can be found from twin studies conducted on females, the

coordinance rate for monozygotic twins is 50% whereas in dizygotic twins the coordinance rate

is 36% (Bole 3). Although ASD is not as common in females there is still a clear connection of

the etiology of ASD to genetics. The sharing of DNA resulting in a higher coordinance rate

indicates that specific genes could be targeted in order to understand the root cause of ASD.

Without specific and balanced signals, the brain of a developing child may suffer due to

errors in neuronal maturation and differentiation. The brain does not fully mature until 25,

however, most of the neuronal malfunctioning occurs at a younger age.​ Glutamate and GABA

affect development of the brain due to their function of inhibiting and exciting action

potentials in neurons. ​These neurotransmitters work through either ionotropic receptors,

GABA​A​, or G protein-coupled receptors, GABA​B​. GABA receptors work similarly through both

types of receptors. GABA​A​ allows negatively charged chloride ions to enter the cell which

hyperpolarizes the membrane potential of the neuron and makes it less likely to send out an

action potential (2-minute Neuroscience). Correspondingly, GABA​B​ is a g-protein coupled

receptor and it works through the opening of a channel that allows positively charged potassium
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ions out of the cell, resulting in the hyperpolarization of the cell (2-minute Neuroscience). Both

receptors result in the same effect of lowering the membrane potential. GABA​A​ receptors let

negative ions in, whereas GABA​B ​lets positive ions out. Overall the cell becomes more negative

compared to the starting point. The receptors and the channels related to the receptors are made

of proteins which are encoded for by DNA. The genetics behind the possible cause of ASD is

that a mutation occurs in a gene relating to the GABAengeric system, causing the

hyperpolarization of the neuron to malfunction. The mutation in the gene will encode the wrong

amino acid, the building block of proteins, and cause the shape of the protein to be altered.

Shaped changes in proteins alters the binding site where the ligand, signaling molecule, would

bind therefore the message will not be sent. In essence any change in the genetic code for a

protein related to inhibitory signals will cause complications such as ASD in the offspring.

The development of the immature brain is critical to the proper functioning of the child.

GABA signaling is one of the first influences on brain growth. “GABA-mediated signaling has

been implicated in most of the developmental steps from cell proliferation to synaptic

integration. As it is the first neurotransmitter active in the immature brain and provides the main

excitatory drive, GABA is poised to serve as an ideal signal to coordinate corticogenesis” (Wang

1). Since GABA is the first signal most neurons receive in an immature state these

neurotransmitters actually have an excitatory effect due to the depolarizing effects on the

neurons. These signals relate to the formation of synapses, area in which the neurotransmitters

are released, because of their early presence. Recent studies have, “demonstrated that GABA

and glutamate decreased net DNA synthesis and the number of progenitor cells that incorporate

BrdU in acute cortical slices” (Wang 2). E-I balance during the developmental stages of the
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brain affect the rate of division in cells. Reduction in cell division will negatively affect the

developing human because the division of cells helps repair damaged tissue and aids the

organisms growth. Without growth and repair of the organism ASD would be more likely

because the immature brain will be damaged, leading to various signaling complications. Along

with the division of cells GABA also, “works as a trophic factor, modulating neuronal migration

and maturation” (Cellot 2). In essence, neuronal migration puts the neurons in the correct

position of the brain. The specific location of the neuron affects how the neurons communicate

with each other; therefore, if the migration is disturbed so are the correct signaling patterns.

Overall GABA can work in multiple ways to lower the action potential of a cell. GABA is

produced early on in the developmental stages so it has a tremendous effect on how the child

evolves. Through this information, it is clear that GABA relates to developmental disorders such

as ASD through its importance in regulating cell signaling.

Works Cited

Action Potential in the Neuron​. https://www.youtube.com/watch?v=oa6rvUJlg7o. Accessed

20 Feb. 2020.

Bole, Kristen. “Study Debunks Autism as a Primarily Genetic Disorder.” ​Study Debunks
Autism
as a Primarily Genetic Disorder | UC San Francisco,​
https://www.ucsf.edu/news/2011/07/98350/study-debunks-autism-primarily-genetic-
disorder​. Accessed 14 Jan. 2020.

CDC, “Data & Statistics on Autism Spectrum Disorder.” ​Centers for Disease Control and
Prevention​, Centers for Disease Control and Prevention, 25 Mar. 2020,
www.cdc.gov/ncbddd/autism/data.html.

Cellot, Giada, and Enrico Cherubini. “GABAergic Signaling as Therapeutic Target for
Autism
Spectrum Disorders.” ​Frontiers in Pediatrics,​ vol. 2, July 2014,
doi:​10.3389/fped.2014.00070​.

Devnani, Preeti A., and Anaita U. Hegde. “Autism and Sleep Disorders.” ​Journal of Pediatric
Neurosciences,​ vol. 10, no. 4, 2015, pp. 304–07, doi:​10.4103/1817-1745.174438​.

Gamma-Aminobutyric Acid (GABA).​

Kang, Eunchai, et al. “Interplay between a Mental Disorder Risk Gene and Developmental
Polarity Switch of GABA Action Leads to Excitation-Inhibition Imbalance.” ​Cell
Reports,​ vol. 28, no. 6, Aug. 2019, pp. 1419-1428.e3

Knifften, Cassandra. “GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3.”

Quaak, Ilona, et al. “The Dynamics of Autism Spectrum Disorders: How Neurotoxic
Compounds
and Neurotransmitters Interact.” ​International Journal of Environmental Research
and Public Health​, vol. 10, no. 8, Aug. 2013, pp. 3384–408,
doi:​10.3390/ijerph10083384​.

Wang, Doris D., and Arnold R. Kriegstein. “Defining the Role of GABA in Cortical
Development.” ​The Journal of Physiology​, vol. 587, no. Pt 9, May 2009, pp. 1873–79,
doi:​10.1113/jphysiol.2008.167635​.
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2-Minute Neuroscience: GABA​. ​https://www.youtube.com/watch?v=bQIU2KDtHTI​.