Biomedical Research

The Molecular Basis of Autism

By Ashray Bangalore

Published 11:59 EST, Fri December, 17th, 2021


Autism is a very complex disorder, as it cannot be categorized by one simple cause or one simple effect. The molecular basis of this disease is not a commonly explored topic, but this review will go over some parts of it. ASD is commonly caused by mutations, both in non-coding genes and through protein-coding sequences. This review will also outline some experiments performed in order to specify certain genes that lead to ASD. Brain structure will be explored and potential cures for ASD will be identified as well.


Autism spectrum disorder (ASD) is a disorder characterized by deficits in social communication and the presence of restricted interests along with repetitive behaviors [1]. The first ever documentation of ASD was done in 1943 by Leo Kanner [2]. Some causes for the disorder include genetic mutations, an overgrowth of the brain known as macrocephaly, and other lesser known causes. Overall, ASD is a pretty rare disease, affecting about 1% of all populations worldwide. Symptoms for diagnosis of ASD include social-communication deficits, and restricted and repetitive interests/behaviors. However, ASD is also linked with other abnormalities such as motor and sensory abnormalities [3]. ASD is a wide-encompassing disorder as there is not a single locus where the disorder occurs. Instead, it is widespread and several regions throughout the body have been identified to cause autism. No widespread treatment exists for ASD yet, treatments such as gene therapy and protein replacement therapy are some potentially widespread therapies that will be discussed in this review. 

Molecular Basis of ASD

Importance of GABA Signalling

Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. It is primarily used to calm down neural responses throughout the nervous system. GABA is synthesized from glutamate and catalyzed by the enzyme glutamic acid decarboxylase [4]. GABA affected by autism has negative effects due to mutations that lead to an inverse effect of the inhibition originally caused. Rather than inhibiting neural signals, patients with autism have GABA receptors that are mutated, allowing for a sensory overload at times that can make them more susceptible to touch based responses. As shown in figure 1, interrupted GABA signalling will lead to less interrupted signals and may even overload the brain through an increased amount of neural connections sent from the hand to the brain. 

Figure 1: A) A schematic showing proper tactile perception of a ball recognized from a hand. Arrows indicate information travelling from the hand to the brain. Red octagons represent inhibited signals within synapses and green lightning bolts represent excitatory signals within synapses. B) As in A, but, arrows show overload of information reaching the brain as a cause of too little inhibition within synapses illustrated by green lightning bolts and a lack of red octagons. Red splatter shows a brain with ASD getting overloaded with information due to mutations in GABRG1, GABRA2, GABRA4, and GABRB1. 

Mutations Correlated with Autism

List of Potential Genes that are Correlated with Autism

Autism is a very complex disease that does not have only one cause to it. Since it has numerous factors, there are multiple genes that affect it as well. Some such genes include GABRG1, GABRA2, GABRA4, and GABRB1, which all are related to GABA signalling in some way or another. Mutations in these gene subunits will affect the inhibition of neural signals and may cause a sensory overload due to the sheer amount of neural signals being sent at once [5].

Proteins Affected by Genetic Mutations Associated with ASD

Since genes code for proteins, they also play an important role. One minor change in a codon can entirely change the proteins being synthesized. An example of a protein affected by asd is CPEB4, a protein involved in coordinating the expressions of hundreds of genes required for neural activity. In one study, rats were found to show signs of ASD linked with defects in the ability to express this protein [6]. Another protein linked gene is CNOT1, which is a commonly mutated gene found in numerous autism patients. One study discovered that variations in this gene led to problems with learning and memory [7].

Details About Brain Structure

Sights of Interest in the Brain

The cortex is made up of 4 lobes: the temporal lobe, the parietal lobe, the occipital lobe, and the frontal lobe. The frontal lobe includes the frontal cortex and all other cortices, along with broci’s area. The temporal lobe contains white matter, part of the lateral ventricle, the tail of the caudate nucleus, and the hippocampal formation. The occipital lobe contains the primary and association visual cortex and is the smallest lobe of the brain [8]. Lastly, the parietal lobe contains the postcentral gyrus, the superior parietal lobule, and the inferior parietal lobule. All the lobes are located in the cerebrum. Other parts of the brain include the brainstem, cerebellum, and amygdala. In terms of function, the frontal lobe controls emotions and regulates them in interpersonal relationships and social situations. 

ASD in the Brain 

Several different brain regions across the brain are listed to show causes of autism. For example, in this study, researchers found that in the cerebellum, a lack of RNF8 led to too many synapses forming in the brain. However, the extra synapses worked and did not cause too many problems for the mice. The mice that did not have the RNF8 gene showed signs of struggling to learn new motor skills, a prevalent factor of ASD [9]. 

ASD out of the Brain

Not just brain – sensory deficits also drive certain behaviors in ASD as well. Manipulating certain senses can lead to ASD, for example messing with the sense of touch to make someone more susceptible to pain may lead to ASD. Somatosensory touch can happen in a number of places on the skin, and thus can lead to more awkwardness in outside scenarios and potentially even a form of ASD. Impacts to the peripheral nervous system will also affect the central nervous system because they are interlinked. ASD affects the link between them by reducing the threshold for the peripheral nervous system to send signals to the central nervous system. 

Potential Treatments for ASD

Treatments that might work

Currently, no existing treatment exists for ASD. However, there have been numerous studies theorizing some potential solutions to the disorder that may lead to some success. One study talks about using GABA A receptor agonists in order to treat tactile overreactivity [10]. These agonists activate the GABA receptors, allowing them to inhibit receptors to counteract the overstimulation of neurons within the brain. 

Gene therapy is a relatively newer method for curing potential autism along with other genetic disorders and diseases. Gene therapy is defined as the treatment of disease by transfer of genetic material into cells [11]. An example of gene therapy would be if someone had a cancerous tumor forming from a genetic mutation. Gene therapy could be used to correct that mutation by rewriting it. Gene therapy works by doctors first delivering a copy of healthy cells with the correct genes into the patient’s system and allowing them to adjust to the body. However, some pitfalls to this method include the developmental nature of the disorder, causing genetic therapy to potentially become ineffective in some cases. Additionally, specific targeting may be difficult such as targeting specific types of neurons.

Protein Replacement Therapy is another potential treatment for ASD as well. As the name suggests, this treatment works by replacing non functioning proteins or proteins that are not working properly. Protein replacement therapy is a newer treatment method, but it may be the next innovative way to cure rare diseases in a much simpler way [12]. Downfalls of this method include the lifespan of proteins, ranging from a few hours to a few weeks. However, future research of protein replacement therapy could lead to a more universal and lasting change in proteins. 


ASD is a complex disorder, consisting of numerous causes and symptoms. Ever since Leo Kanner discovered the first case, the prevalence of the disorder has increased substantially. Various mutations, both genetic and protein based, can induce ASD in children and adults. The molecular basis of Autism is rooted in chemical changes within the brain, both with responses to stimuli and receptors not firing off correctly. Overall, the brain is the most affected part of the body by ASD, physically and psychologically. Some potential treatments are discussed in this review, and they have potential to work through further testing. 

Ashray Bangalore, Youth Medical Journal 2021


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