Autism Spectrum Disorder: Excitatory/Inhibitory Imbalance Among Children

Introduction

According to the American Psychiatric Association and recent surveys, autism spectrum disorder (ASD) is
a group of complex neurodevelopmental disorders characterized by deficits in social communication and
interaction as well as stereotyped behaviors. It has been found that there are more males than females
with ASD and clinical differences between the sexes have been observed. The prevalence of ASD has
also been documented to be on the rise.

The research on autism spectrum disorder (ASD) has yielded various findings, with MRI studies showing
inconsistent associations between brain abnormalities and autism. Functional MRI during language and
memory processing tasks has suggested a lower level of connectivity and information integration across
cortical and other networks as the potential neural basis for disrupted language and brain activity in
ASD. Chromosome abnormalities have been found in about 7% of autistic disorder cases, but their
implications for etiology are unclear. Many different genes have been implicated in the ASD phenotype,
suggesting that both genetic and environmental factors may play crucial roles.

By examining different clinical research and investigations, this journal strives to provide a
comprehensive understanding about the excitatory/inhibitory imbalance of ASD among children.

Models of Excitatory/Inhibitory Imbalance in Autism Spectrum Disorder

The theory of excitatory/inhibitory imbalance in autism spectrum disorder (ASD) was proposed by
Rubenstein and Merzenich in 2003. This suggests that an increase in excitation relative to inhibition may
lead to hyper-excitability of cortical circuits, which could explain the observed reduced GABAergic
signaling in individuals with ASD. Loss of inhibition could also result in cognitive imprecision due to
increased "noise"during learning, as inhibition is known or believed to help sharpen excitatory
responses.

Other studies have proposed a different hypothesis than the excitatory/inhibitory imbalance theory.
Some suggest that at least some cases of autism spectrum disorder (ASD) may be characterized by a
reduction in the ratio between excitation and inhibition. Multiple studies have reported an E/I
neurotransmission imbalance in cortical neurons, using dysfunctional glutamatergic and GABAergic
neurotransmission, with altered glutamine levels and/or abnormal GABA/creatine levels in brain tissue
or plasma being relevant findings. These studies include research from Vignoli et al., Carlson, Spooren et
al., Gao and Penzes, Dickinson et al., Lee et al., Al-Otaish et al., Goel and Portera-Cailliau, Port et al.,
Bruining et al., Culotta and Penzes.

Moreover, a recent study found that high levels of glutamate/glutamine were associated with altered
functional connectivity in important brain regions for autism spectrum disorder (ASD), such as the dorsal
anterior cingulate cortex, and insular, limbic, and parietal regions. This study was conducted by Siegel-
Ramsay et al. in 2021.
An imbalance between excitation and inhibition may result from increased glutamatergic activity and
decreased GABAergic signaling. Studies have shown a possible link between genes involved in
neurogenesis or synaptogenesis and this E/I imbalance, as well as alterations in genes coding for
glutamatergic receptors or synaptic proteins. Neurexins and their binding neuroligins, which help form
excitatory and inhibitory synapses, are also implicated in ASD. Heterozygous deletions of neurexin-1α
gene exons have been detected in individuals with ASD, but the functional significance of this deletion is
still not clear according to Frye (2018).

Clinical Implication

There have been several studies that suggest that GABAergic neurons and circuits may be affected in
ASD. GABA neurotransmission is important for developmental processes such as cell proliferation,
differentiation, synapse maturation, and cell death. Researchers have found evidence of dysfunctional
GABAergic signaling early in development leading to an imbalance between excitatory and inhibitory
neuronal circuits in individuals with ASD.

Studies have examined the use of GABAergic modulators in individuals with ASD. In one study, an open-
label trial tested the safety and effectiveness of STX209, a type of arbaclofen. The results showed
improvements in various outcome measures. This prompted a 12-week randomized controlled trial of
STX209 which showed that it was more effective than placebo, although the results did not reach
statistical significance.

In a randomized, double-blind, placebo-controlled trial conducted by Lemonnier et al. (2012), the

efficacy of bumetanide treatment was evaluated in 60 French children with ASD. The group that
received bumetanide showed a statistically significant improvement in the mean total score of the
Childhood Autism Rating Scale compared to the placebo group after 3 months.

Additionally, Lemonnier et al. (2012) found that bumetanide treatment improved scores on the Autism
Diagnostic Observation Schedule, although the improvement was not statistically significant. In a
randomized trial conducted by Du et al. (2015), treatment with bumetanide combined with ABA training
led to better outcomes compared to ABA training alone in 60 Chinese children with ASD who were
between 2.5 and 6.5 years old, with a mean age of 4.5 years.

Another study by Lemonnier et al. (2017) was conducted, which was a double-blind, randomized
controlled multicenter dose-ranging study. The authors found that bumetanide treatment had positive
effects on all age and severity groups of ASD patients based on CARS scores. However, it remains unclear
if patients with more severe ASD symptoms have a greater response to bumetanide treatment. Overall,
these findings suggest that bumetanide may be a promising avenue for treating core symptoms of ASD;
however further studies are needed to confirm its efficacy.

Conclusion

The available medications that target the E/I imbalance in ASD mainly improve irritability symptoms, but
some like bumetanide show potential for improving social and communication difficulties as well.
Treatment response and tolerability vary among different age groups of individuals with ASD. Therefore,
future studies need to carefully consider symptom severity at baseline and placebo response to stratify
patients according to their symptoms and associated biomarkers. It is important to recognize the
differences between symptom levels such as social avoidance and lack of reciprocity in order to develop
effective treatment strategies for each individual's unique needs.

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