Autism & Sensory Processing Disorder

This is not a comprehensive list, simply some articles I have found along the way. See immune function, mitochondrial dysfunction, microbial imbalances, seizures, ADHD, speech & language, movement disorders, sensory processing disorder, obsessive-compulsive disorder, methylation, metals, and EMF’s tab for additional information related to glutamate and autism.

Favorite article on the role of glutamate in autism: http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/

Great article linking autism symptoms to excess glutamate and glutamate dysfunction: http://www.ageofautism.com/2011/03/autism-and-glutamate-dysfunction-avoid-the-cause-race-to-the-cure.html

Amazing flowchart on how free glutamate affects autism spectrum disorder, by Carol Hoernlein of MSG Truth http://www.msgtruth.org/images/Theory%20of%20Autism-Simplified.pdf

Here is a great video on methylation and the role of glutamate in autism.

Glutamate, Diet, and Autism

“A study by Stanford University investigators suggests that key features of autism reflect an imbalance in signaling from excitatory and inhibitory neurons in a portion of the forebrain, and that reversing the imbalance could alleviate some of its hallmark symptoms.” “The new study shows that decreasing that ratio restores normal behavior patterns in a strain of lab mice bioengineered to mimic human autism”
Please note the “RESTORES NORMAL BEHAVIOR PATTERNS” quote!😍
https://www.sciencedaily.com/rel…/2017/08/170802152544.htm

Recently released article indicates a newly discovered neuron circuit that directly connects the gut to the brain. Glutamate is the neurotransmitter reacting between sensory cells in the gut lining and sensory nerves communicating with the vagal nerve. This process happens “within tens to hundreds of milliseconds, a time scale typical of synaptic transmission rather than neuropeptide signaling”.

“These findings, published today in Science Translational Medicine, add heft to the long-standing theory that autism stems from too much excitation in the brain1. They also hint that treatments that restore the balance between excitation and inhibition could ease social difficulties in people with autism.”“I think this work is important because it provides the most direct evidence so far that acutely changing the ratio of excitation to inhibition immediately improves autistic-like behaviors,” “Boosting inhibition and turning off excitation also make the mutant mice less hyperactive. The results are “striking,” says Susanne Ahmari, assistant professor of psychiatry at the University of Pittsburgh.” https://www.scientificamerican.com/article/scientists-use-light-to-turn-off-autism-symptoms-in-mice/

Abstract:http://stm.sciencemag.org/content/9/401/eaah6733

“It was initially thought that autistic children had fewer glutamate receptors, but subsequent studies, including one from the prestigious journal Neurology published in 2001, showed that autistic children, in fact, have more glutamate receptors than normal controls. Furthermore, they are genetically predisposed to have more. So autism is another hyper-glutamate condition.” http://nancymullanmd.com/glutamate-and-gaba-balance/

“The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.” Alteration of Plasma Glutamate and Glutamine Levels in Children with High-Functioning Autism https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187770/

“Our findings support associations between the SLC25A12 gene variant and the risk of childhood ASD, and between the GRM8 gene variant and the severity of language impairment in the Chinese Han population.” A pilot Study on glutamate receptor and carrier gene variants and risk. Liu, J., Yan, J., Qu, F. et al. A pilot study on glutamate receptor and carrier gene variants and risk of childhood autism spectrum. Metab Brain Dis (2023). https://doi.org/10.1007/s11011-023-01272-w

“This neuroinflammation upsets the balance between excitatory and calming neuro-transmitters, causing the glutamate system to become overexcited and GABA production to be curtailed.  This results in the development of autistic symptoms and other neurological disturbances such as seizures.” “Two biomarkers of this glutatmate excitotoxicity are mitochondrial dysfunction involving 1) viral exposures which damages the mitochondrial membrane resulting in formation of swellings (dendritic beading) along the nerve dendrites and 2) the formation of lipid rafts, ceramides within the cells impairing mebrane function.” http://www.ageofautism.com/2009/07/solving-the-autism-puzzle-the-fatty-acid-question-and-big-fat-neurons.html

“Of particular concern is the toxic effects of these excitotoxic compounds on the developing brain. It is well recognized that the immature brain is four times more sensitive to the toxic effects of the excitatory amino acids as is the mature brain. This means that excitotoxic injury is of special concern from the fetal stage to adolescence. There is evidence that the placenta concentrates several of these toxic amino acids on the fetal side of the placenta. Consumption of aspartame and MSG containing products by pregnant women during this critical period of brain formation is of special concern and should be discouraged. Many of the effects, such as endocrine dysfunction and complex learning, are subtle and may not appear until the child is older. Other hypothalamic syndromes associated with early excitotoxic lesions include immune alterations and violence dyscontrol.” http://www.jpands.org/hacienda/article27.html

“Rhythmic Movement Training in Autism- The rhythmic exercises stimulate many of the areas of the brain which are damaged in autism and improve their function. For optimal effect of RMT the gastrointestinal function need to be addressed. Otherwise toxins, peptides and allergens will cross the mucosa and be transported from the bowels and pass the blood brain barrier, causing continued brain damage by inflammatory and toxic reactions of the brain. It happens quite frequently that the child gets over stimulated by rhythmic exercises and reacts with restlessness and hyperactivity. Such reactions may occur also in children with ADD and ADHD. The cause of these reactions is probably an inability of the brainstem to filter stimulation from the tactile, vestibular and proprioceptive senses. Excessive stimulation reaches the brain and activates its GLUTAMATE RECEPTORS. Glutamate is the most widespread transmitter substance in the brain. If there is an inability to convert stimulating glutamate into inhibiting GABA the child will soon become restless and start wriggling and try to get away. Therefore a child with autism should be on a diet free from gluten, casein and preferably soy. This is especially important for children who do rhythmic exercises. Self stimulating Behavior – If the concentration of glutamate rises to toxic levels outside the neurons they start firing uncontrollably causing self stimulating behavior or stims. These are repetitive body movements that stimulate one or several senses in a regulated manner. They include- hand flapping, body spinning or rocking, mechanically lining up or spinning toys, repeating rote phrases, echolalia, i.e. mechanically repeating what others say
perseveration, (repetition of a particular response, such as a word, phrase, or gesture, despite the absence or cessation of a stimulus). Rhythmic exercises improve speech – Almost all children with autism or ASD have more or less obvious difficulties doing simple active rhythmic exercises. Such difficulties are also common in children with ADD, ADHD and late speech development and indicate a damage of the cerebellum. Such damage is especially common in autism and has been confirmed by many research studies. Damage of the cerebellum may prevent speech from developing since speech cannot develop if the speech areas of the left hemisphere don´t get sufficient stimulation from the cerebellum. By stimulating the cerebellum with rhythmic exercises speech development will be promoted. The Purkinje cells of the cerebellum use GABA as a transmitter substance and the rhythmic exercises will in the long run cause more GABA to be produced provided inflammation of the cerebellum and glutamate accumulation can be prevented by an appropriate diet. http://www.blombergrmt.com/autism-and-rhythmic-movement-training/

Further studies of GABA and Glutamate imbalances in autism are important challenges for future research https://onlinelibrary.wiley.com/doi/full/10.1111/apa.14589

“Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder.” http://www.ncbi.nlm.nih.gov/pubmed/11706102

“Collectively, these results are consistent with the hypothesis suggesting the role of the glutamatergic disturbances on the pathogenesis of autism.”
https://www.frontiersin.org/articles/10.3389/fnmol.2018.00418/abstract

There is strong evidence that metabotropic and ionotropic glutamate receptors are affected in autism spectrum disorders (ASD), but there are few candidate genes indicating involvement of these receptors. This suggests that glutamate receptor dysregulation may primarily be involved in the expression of ASD, but is an uncommon etiology. Directly implicated in models of fragile-X with ASD phenotypes is metabotropic glutamate receptor type 5 (mGluR5), which appears to be an effective pharmacologic target in a number of models of ASD. The review of other ASD models demonstrates that there is also evidence of a role for kainate, NMDA, and AMPA receptors in the neuropathophysiology of ASD, though the relationship between dysfunction in those receptors and ASD-associated phenotypes is not well understood. Current models indicate a way forward to delineate the role of glutamate receptors in ASD. Further development of preclinical models focusing on glutamate receptors may provide tools to target a clinically important subset of ASD symptoms. https://www.ncbi.nlm.nih.gov/pubmed/21315104

“This is the first time, in humans, that a neurotransmitter in the brain has been linked to autistic behavior. This theory — that the GABA signaling pathway plays a role in autism — has been shown in animal models, but until now we never had evidence for it actually causing autistic differences in humans,” http://consumer.healthday.com/cognitive-health-information-26/autism-news-51/autism-neurotransmitter-harvard-release-batch-2449-706297.html

“When GABA is low, glutamate is high and vice versa. So in order to increase gamma-aminobutyric acid it’s not simply a matter of bringing it up, you must also focus on reducing the excess glutamate. The goal is to achieve balance between the two. You might think of glutamate as the accelerator and GABA as the brakes. Both are equally important.” (http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/)

“One of the biggest contributors to an imbalance in GABA and glutamate is the presence of excitotoxins in the diet. Many foods and nutritional supplements contain the excitotoxins (glutamate, glutamic acid, glutamine, aspartate/aspartic acid, and cysteine) or they contains substances that can prompt the body to produce them. These foods and substances should be avoided by anyone trying to balance their GABA and glutamate levels and anyone who tends to generally lean towards excess glutamate.” (http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/)

“Dr. Amy Yasko, an expert in autism, tells parents with children who have autism that if they take only one step in her recovery program that the most important element is to eliminate excitotoxic foods that increase glutamate levels. This one step alone can provide dramatic improvements in STIMS. Thus, demonstrating the profound impact that excitotoxins have on brain function.” http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/)

“In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission, with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of the structure and function of glutamate receptors, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the development of novel drugs for ASD treatment, and reports on glutamate- related clinical trials. We will also present promising new techniques using human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotypes, cellular responses and glutamate involvement in ASD.” Glutamate-mediated signaling and autism spectrum disorders: emerging treatment targets. https://www.ncbi.nlm.nih.gov/pubmed/24410563

“Previous studies from the Huganir and Wang teams showed that mutations in glutamate receptor interacting protein 1 (GRIP1) contribute to increased severity in autism social deficits¹. These autism-associated mutations were found to cause abnormal trafficking of AMPA receptors in neurons. The researchers then generated and conducted behavioral studies on mice that carry the same mutation. The mutant mice exhibited severe defects in social interactions, similar to individuals with autism who carry this mutation. Future plans include testing whether drugs that modulate AMPA receptor functions can improve social deficits in these mice. The researchers hope the results will provide valuable insights into the regulatory mechanisms of autism social behaviors and guide the development of novel AMPA-receptor-based therapies to correct social deficits in autism.” The role of glutamate receptor interacting proteins in autism https://sfari.org/funding/grants/abstracts/the-role-of-glutamate-receptor-interacting-proteins-in-autism

“Multiple regression analysis revealed associations between reduced GABA level, neuroinflammation and glutamate excitotoxicity. This study indicates that autism is a developmental synaptic disorder showing imbalance in GABAergic and glutamatergic synapses as a consequence of neuroinflammation.” GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders http://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-014-0189-0

“Insufficient levels of GABA result in nervousness, anxiety and panic disorders, aggressive behavior, decreased eye-contact and anti-social behavior, attention deficit, problems with eye-focusing (like that seen in autistic children when both eyes are focused inward towards the nose or waver back and forth in a horizontal or vertical movement), chronic pain syndromes and much more. It may also contribute to GERD as it is needed to help regulate the lower part of the esophagus.” (http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/)

“This neuroinflammation upsets the balance between excitatory and calming neuro-transmitters, causing the glutamate system to become overexcited and GABA production to be curtailed.  This results in the development of autistic symptoms and other neurological disturbances such as seizures.” http://www.ageofautism.com/2009/07/solving-the-autism-puzzle-the-fatty-acid-question-and-big-fat-neurons.html

“Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models.” “In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder” The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134390/

“Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD” Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism https://www.ncbi.nlm.nih.gov/pubmed/28072412

“The autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders that have been increasing in incidence since the 1980s. Despite a considerable amount of data being collected from cases, a central mechanism has not been offered. A careful review of ASD cases discloses a number of events that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link between excessive vaccination, use of aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis, and abnormal formation of the developing brain. It has now been shown that chronic microglial activation is present in autistic brains from age 5 years to age 44 years. A considerable amount of evidence, both experimental and clinical, indicates that repeated microglial activation can initiate priming of the microglia and that subsequent stimulation can produce an exaggerated microglial response that can be prolonged. It is also known that one phenotypic form of microglia activation can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate and quinolinic acid. Studies have shown that careful control of brain glutamate levels is essential to brain pathway development and that excesses can result in arrest of neural migration, as well as dendritic and synaptic loss. It has also been shown that certain cytokines, such as TNF-alpha, can, via its receptor, interact with glutamate receptors to enhance the neurotoxic reaction. To describe this interaction I have coined the term immunoexcitotoxicity, which is described in this article.” A possible central mechanism in autism spectrum disorders, part 1. https://www.ncbi.nlm.nih.gov/pubmed/19043938

“Auism spectrum disorder (ASD) now affects one in 68 births in the United States and is the fastest growing neurodevelopmental disability worldwide. Alarmingly, for the majority of cases, the causes of ASD are largely unknown, but it is becoming increasingly accepted that ASD is no longer defined simply as a behavioral disorder, but rather as a highly complex and heterogeneous biological disorder. Although research has focused on the identification of genetic abnormalities, emerging studies increasingly suggest that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in ASD. This review summarizes the investigations implicating autoimmunity and autoantibodies in ASD.” https://www.ncbi.nlm.nih.gov/m/pubmed/28340985/

MSG inducing obesity, leaky gut, and the inflammatory process. New study:
“A mouse model of chronic obesity induced by monosodium glutamate treatment was established. At postnatal week 15, pathological changes including in small intestinal epithelial cells, were analyzed in chronically obese mice compared with controls. Numerous gaps were identified between small intestinal epithelial cells in chronically obese mice, and levels of both desmosomal and tight junction proteins were significantly lower in their small intestinal epithelial cells. Additionally, numbers of intestinal inflammatory cells, particularly macrophages, were significantly increased in chronically obese mice, as were levels of the inflammatory factors, TNF-alpha and IL1-beta, in blood samples from the mouse model. These findings suggest that functional deterioration of adhesion structures between small intestinal epithelial cells causes gastrointestinal barrier function failure, leading to a rise in intestinal permeability to blood vessels and consequent systemic inflammation, characterized by macrophage infiltration.”
http://www.nrcresearchpress.com/doi/abs/10.1139/apnm-2018-0560

http://dramyyasko.com/wp-content/uploads/2010/06/17-A1-Excitotoxins.pdf

http://www.dramyyasko.com/wp-content/uploads/2011/08/The-Role-of-Excitotoxins-in-Autistic-Type-Behavior.pdf

Why are more males affected with Autism?

Is it possibly because estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition? http://www.ncbi.nlm.nih.gov/pubmed/23835908

“One of the enigmas of autism is why it occurs in males more often than females. Actually there are a number of toxins that have this gender selectivity. Studies have shown, for example, that both mercury and monosodium glutamate (MSG) have greater neurotoxicity in males than females.127 The reason appears to be the enhancing effect of testosterone on both substances’ toxicity.128,129
Glutamate is the most abundant neurotransmitter in the brain and operates through a very complex series of receptors (3 major inotropic receptors- NMDA, AMPA and kainite receptors, and 8 metabotropic receptors). As stated, the presence of glutamate outside brain neurons, even in very small concentrations, is brain cell toxic. Because of this, the brain is equipped with a very elaborate series of mechanisms to remove glutamate quickly, primarily by utilizing glutamate uptake proteins (EAAT1-5). Mercury, aluminum, free radicals, lipid peroxidation products and inflammatory cytokines can easily damage these. 130,131
One of the important ways glutamate regulates neuron function is by allowing calcium to enter the cell and by the release of calcium within cell storage depots. When calcium (glutamate operated) channels are opened, the calcium flows in as a wave of concentrated calcium. These are referred to a calcium waves or oscillations. They regulate a number of neuron functions, one of which plays a vital role in brain development.
During brain development, the future neurons are lined up along membranes within the core of the undeveloped brain. These cells must migrate outwardly to reach their final destination and they do so by guided chemical signals mainly released by microglia and astrocytes. These trillions of connections also develop during a process called synaptogeneis, and use many of the same signals.
Studies have shown that the calcium waves cause developing brain cells to migrate, which is essential for development of the brain (it forms the architectonic structures and functional columns of the brain).132 Interestingly, testosterone also affects embryonic brain cell migration by regulating calcium waves, and mercury, probably by stimulating glutamate release, does the same thing.133 Estrogen reduces calcium oscillations and stops the migration. Other chemical signals in the brain also play a role (reelin).
If calcium oscillations are not properly regulated, that is- there are too many calcium oscillations, the brain develops abnormally. Testosterone and glutamate have an additive effect on these calcium waves. In this way, testosterone enhances the damaging effect of excessive glutamate and mercury.
Studies have shown that higher doses of MSG during brain formation can cause abnormalities of brain development that closely resemble mercury poisoning and the toxic effects of high levels of inflammatory cytokines.76 Interestingly, vaccination has been shown to significantly increase the toxicity of several other neurotoxins, so much so that they can trigger brain cell destruction or synaptic loss even when subtoxic concentrations of the toxicants are used. Testosterone aggravates this toxicity as well.
Studies of autistic children show an elevated level of androgens in most, even in female autistic children.134 In general, androgens, such as testosterone, enhance neurological injury and estrogens tend to be protective of the brain.135 http://www.russellblaylockmd.com/

“Males also have a higher concentration of microglia earlier in life compared to females. This will make them more vulnerable to vaccines and immune activation. Microglia signal additional glutamate, allowing for increased sensitivity to glutamate. ” Males have overall more microglia early in postnatal development (postnatal day (P) 4), whereas females have more microglia with an activated/amoeboid morphology later in development, as juveniles and adults (P30-60). Finally, gene expression of a large number of cytokines, chemokines and their receptors shifts dramatically over development, and is highly dependent upon sex.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296888/

Neuroprotection of estrogen from glutamate: https://www.ncbi.nlm.nih.gov/m/pubmed/26955967/

The role of glutamate in sensory issues: Many struggling with sensory processing disorder (SPD) or sensory issues often complain of yeast or inflammation triggering the issues, but it may very well be the surge of glutamate associated with these issues, that actually causes the changes in the sensory system. The cells signal the release of glutamate in response to inflammation and if you lean towards excess glutamate or have trouble converting glutamate to GABA, you will likely see excitotoxic damage and sensory issues.

“Glutamate is a neurotransmitter that regulates over 50% of our nervous system, which includes our sensory system. Some of the function of the glutamate receptors on our cells is to receive input from our environment (i.e. senses our environment) and translate this information to a signal so that our brain can transmit to the body of how to respond to that signal input. From how we interpret what we see or hear to how we respond to our food, the glutamate receptors make up a large part of our sensory system. When the glutamate receptor signals are not regulated, our sensory system can become dysregulated and the information transmitted is not an appropriate response to the environmental input. In other words, our sensory system can become out of sync and signal output is not a functional response to signal input. Anxiety is a good example of the response of our body not being a functional response to an environmental trigger (input). Auditory processing dysregulation may result in sounds being amplified, as another example.” -Dr. Reid

“The toxins created by Candida can stimulate surges of glutamate production. Hundreds of other toxins can produce this same surge in glutamate activity, including mold toxins, bacterial toxins, Lyme, and organic solvents.” http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/

Other:

“GABA blocks impulses between nerve cells in the brain. Low levels of GABA may be linked to anxiety or mood disorders, epilepsy and chronic pain. It counters glutamate (the upper neurotransmitter), as the two mediate brain activation in a Yin and Yang manner. People take GABA supplements for anxiety.“In normal behavior, the brain is balanced between excitation and inhibition,” Dr. Kim said. “But when the inhibition is decreased, the balance is broken and the brain becomes more excited causing abnormal behavior.“We showed that cognitive and social deficits induced by an Arid1b mutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies.”Next steps for Dr. Kim and his team are to even further refine the specific mechanism for autism and intellectual disability and to identify which of the many GABA neurons are specifically involved. Dr. Kim’s research was supported by a $1.7 million grant from the National Institute of Neurological Disorders and Stroke and a $400,000 Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health.” https://www.newswise.com/articles/breakthrough-research-suggests-potential-treatment-for-autism-intellectual-disability

“Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study we used mutant/knock-out mice of Shank2 (Shank2-/-), Shank3 (Shank3αβ-/-), and Cntn4 (Cntn4-/-) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. “Interestingly, even though Cntn4-/- mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4-/- mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.” https://www.frontiersin.org/articles/10.3389/fnmol.2018.00212/abstract

Zinc-  New study presents a working model that could point to a better understanding of autism’s underpinnings. “The new study, led by Stanford neuroscientists John Huguenard, PhD, and Sally Kim, PhD, and then-graduate student Huong Ha, PhD, showed that zinc is required for the proper behavior of two related proteins, Shank 2 and Shank 3, that hang out at most synapses in the brain. Among their duties, Shank 2 and Shank 3 can reshuffle the subunits of a receptor that dots the receiving end of most nerve cells. This receptor gets tripped off by an incoming chemical signal called glutamate.
In the developing brain, glutamate receptors undergo a process of maturation in the form of internal alterations that are catalyzed by Shank 2 and Shank 3. The substitution of one type of subunit for another type in these receptors endow the receptor with more-prolonged signaling strength, a better “memory” of how often it’s been previously tripped off by the arrival of a glutamate molecule, and a correspondingly more-pronounced propensity to respond heartily to such chemical messages in the future. (This collection of characteristics, which neuroscientists call “plasticity,” is the molecular essence of memory and learning.)
Kim, Huguenard, Ha and their colleagues showed that zinc is absolutely necessary to this development-associated maturation of glutamate receptors by Shank 2 and Shank 3. When triggered by glutamate, a receiving nerve cell opens itself to a temporary but substantial influx of zinc, molecules of which bind to Shank 2 and Shank 3. This, in turn, spurs those two proteins’ active reshuffling of the cell’s glutamate-receptor molecules — an essential and permanent step in the brain circuitry’s development.
Glutamate-receptor maturation is particularly critical in late fetal and early-childhood brain development, when synapses are being formed at an amazing rate. And zinc deficiency is especially pronounced in the very youngest patients diagnosed with ASD. So it’s only natural to ask whether zinc supplementation can stave off the syndrome.” https://scopeblog.stanford.edu/2018/11/12/is-zinc-the-link-to-how-we-think-some-evidence-and-a-word-of-warning/

Immune Abnormalities in Autism Spectrum Disorder—Could They Hold Promise for Causative Treatment?
“There is evidence of altered immune function both in cerebrospinal fluid and peripheral blood. Several studies hypothesize a role for neuroinflammation in ASD and are supported by brain tissue and cerebrospinal fluid analysis, as well as evidence of microglial activation. It has been shown that immune abnormalities occur in a substantial number of individuals with ASD”
What else is a byproduct of microglial activation? Glutamate

https://link.springer.com/article/10.1007/s12035-017-0822-x