Health/Hot topics

Unlocking the Mind: How Wnt Pathways Shape Brain Development and Schizophrenia Risk

Posted on by smohame4 / 0 Comment

Schizophrenia is a complicated brain health condition that affects millions of people worldwide. But even though we know a lot about it, we still don’t fully understand what causes it. That being said, recent research has zeroed in on the Wnt signaling pathway and its connection to Glycogen Synthase Kinase 3 (GSK3) as key players in brain development and schizophrenia. Understanding how these pathways work doesn’t just help us understand the science behind schizophrenia, it also opens doors for new treatment options.

The Role of Wnt in Building a Healthy Brain

The Wnt signaling pathway is kind of like a traffic control system for brain development. It helps guide important processes like cell differentiation, neuron formation, and survival. There are two main branches:

  • The canonical pathway, which controls gene expression through β-catenin.

  • The non-canonical pathways, which regulate things like cell movement and calcium signaling.

Normally, when Wnt isn’t around, GSK3β tags β-catenin for destruction before it can activate any genes. But when Wnt binds to its receptors (Frizzled and LRP5/6), β-catenin is protected from being broken down. This allows it to reach the nucleus, where it turns on genes crucial for brain function.

Figure 1. This shows  the wnt signaling pathway, specifically the canonical signalng where Wnt binds Frizzled (FZ) and LRP5/6, activating Disheveled (DVL) and inhibiting β-catenin degradation. Stabilized β-catenin enters the nucleus, activating gene expression.

How the Environment Affects Wnt and Schizophrenia

It’s not just genetics that shape brain health. Environmental factors can mess with Wnt signaling too, especially before birth. Things like prenatal infections, malnutrition, and toxin exposure can alter Wnt-related gene expression, which can rewire the brain in ways that increase schizophrenia risk.

For example, if a pregnant person gets an infection, their immune response can disrupt Wnt/GSK3 signaling in the developing brain, leading to changes similar to what we see in schizophrenia patients[1]. And it’s not just infections—pollutants like heavy metals and endocrine disruptors have been found to impact the epigenetic regulation of Wnt genes, which could contribute to the disorder later in life[2].

Figure. 2. this demostrates how schizophrenia arises from genetic factors (e.g., DRD2, DISC1, GRM3), epigenetic modifications, and environmental influences (e.g., stress, diet, substance use) affecting the gut, immune, and brain systems. Dysregulation of dopamine, serotonin, GABA, and glutamate contributes to symptoms.

Can We Lower the Risk of Schizophrenia?

While genetics play a role, research shows that lifestyle and environmental choices might help lower the risk. Some key strategies include:

  • Prenatal Care: Getting proper medical care during pregnancy, including vaccines and good nutrition, may help protect fetal brain development.

  • Reducing Toxin Exposure: Avoiding harmful chemicals like lead and pesticides could help keep Wnt signaling on track.

  • Dietary Support: Nutrients like omega-3s, folate, and vitamin D have been linked to healthy Wnt activity and brain growth[3].

  • Early Intervention: Spotting early signs of schizophrenia risk could lead to targeted treatments, like cognitive training or medications that support Wnt signaling[4].

Schizophrenia is still full of unknowns, but the more we learn about the Wnt and GSK3 pathways, the closer we get to better treatments and even prevention strategies. Understanding brain health on a molecular level is the first step toward changing the way we see and treat mental illness.

 

Footnotes

[1] Singh KK. An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clin Genet. 2013; 83(6): 511-517.

[2] De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene. 2006; 25(57): 7545–7553.

[3] Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002; 297(5580): 365–369.

[4] Gould TD, Einat H. β-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology. 2007; 32(10): 2173–2183.

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Can Rats Have Schizophrenia? Current Animal Models of Schizophrenia

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Artstract created by Ren Lind

Schizophrenia is a disorder that can significantly affect a human’s life, but can we mimic the symptoms in rats? How can researchers tell if the rats are experiencing something cognitively, such as hallucinations or delusions? First, let’s dive into Schizophrenia and a theory around its pathology to understand the animal models for this disorder.

Schizophrenia 

Schizophrenia is beginning to be understood as a neurodevelopmental disorder. [1] There are positive and negative symptoms. Positive symptoms do not refer to positive as good symptoms, but rather positive symptoms are hallucinations, delusions, and other thought distortions. Negative symptoms are seen as social withdrawal, significant decrease in motivation, and a lack of or excessive movement, to name a few. Cognitive dysfunction is also present in people with Schizophrenia. [2] People with Schizophrenia typically do not present symptoms until late adolescence to middle adulthood.

Researchers Michaud and Pourquié hypothesize that developmental pathways are disrupted in people with Schizophrenia. They specifically refer to the Wnt pathway, a process in the brain that is important for neuron connection development, promoting brain growth during development and adult neural brain circuitry function. With this in mind, let’s consider the common animal models for Schizophrenia.

Animal Models

Researchers can use animal models to study treatment options, pathology, and symptoms for human conditions without using human subjects. Rats are the animal most commonly used for Schizophrenia models. Researchers will modify the rat to induce Schizophrenia-like symptoms.

We can’t ask a rat if it’s experiencing hallucinations or other Schizophrenia symptoms, but their behavior can be analyzed to determine if something is happening. Behaviorally, researchers use various behavioral tests to look at increased anxiety behaviors, deficits in learning and memory, withdrawn social behaviors, and excessive or lack of movement in new environments, among other characteristics. Anatomically, researchers can analyze brain activity and anatomy to determine differences associated with Schizophrenia.

There are four main categories for creating animal models for Schizophrenia: physically modifying neural development, external stress, medication, and altering gene expression. [3]

[4] Figure 1: Overview of Schizophrenia model types, the rat characteristics, and tests for analyzing their behaviors.

Developmentally, researchers put a small cut in the rat’s brain 7 days after it’s born. Another model injects a pregnant rat with Maternal Immune Activation (MIA) to turn on immune responses that are similar to that of human sickness, and the infant rat will be the subject. Both of these models elicit the behaviors mentioned earlier during the rat’s late adolescence to adulthood, which is a similar age range to human development of Schizophrenia.

Because developmental changes can elicit Schizophrenia-like behaviors in a similar age range, it is further evidence that Schizophrenia is a neurodevelopmental disorder.

Inducing post-weaning stress or social isolation will create similar behaviors. Researchers can use a variety of drugs to induce psychosis in rats, but typically, the social behaviors associated with Schizophrenia will not be present in these models. Several risk genes can be expressed or not expressed to induce Schizophrenia in rats and offer promising research opportunities for understanding the genetic background of Schizophrenia.

These animal models are not a “perfect fit” for mimicking Schizophrenia. No animal model can completely portray the nuances of human experience, and many of these behaviors in the rats overlap with other neurodevelopmental model behaviors, however, it is still a valuable research method. There are many gaps in knowledge about Schizophrenia in research, so any progress we can make with the resources we have will help develop efficient therapies, social understanding, and medical resources.

Resources 

[1] Michaud, J. L., Pourquié, O. (2013). An emerging role for Wnt and GSK3
signaling pathways in schizophrenia. Clinical Genetics, 83, 511-517. doi: 10.1111/cge.12111

[2, 3] Winship, I. R., Dursun, S. M., Baker, G. B., Balista, P. A., Kandratavicius, L., Maia-de-Oliveira, J. P., Hallak, J., & Howland, J. G. (2019). An Overview of Animal Models Related to Schizophrenia. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 64(1), 5–17. https://doi.org/10.1177/0706743718773728

[4] Sánchez-Hidalgo, Ana & Martín Cuevas, Celia & Crespo-Facorro, Benedicto & Garrido Torres, Nathalia. (2022). Reelin Alterations, Behavioral Phenotypes, and Brain Anomalies in Schizophrenia: A Systematic Review of Insights From Rodent Models. Frontiers in Neuroanatomy. 16. 10.3389/fnana.2022.844737.

Health

Lithium’s Dual Role in Schizophrenia and Mood disorders

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Schizophrenia is a chronic mental disorder that affects how an individual thinks, behaves, and perceives reality. While it presents with a range of symptoms, it is most commonly characterized by hallucinations, delusions, and difficulty expressing emotions. In addition to these symptoms, schizophrenia also impacts cognitive function, social interactions, and daily living, making it one of the leading causes of disability worldwide.1

Although current treatments can significantly reduce psychotic symptoms, they do not fully address the underlying biological mechanisms of the disorder. Research suggests that schizophrenia is rooted in brain development and neural connectivity, with disruptions in specific signaling pathways, such as the Wnt pathway, potentially playing a role in its development.1 Understanding these mechanisms could pave the way for more effective treatments in the future.

The Basics of Wnt Signaling

Wnt signaling is a crucial pathway involved in cell development, differentiation, and neural function. It is divided into three main pathways:

  1. Canonical Wnt Pathway: This pathway is β-catenin-dependent and involves glycogen synthase kinase 3 beta (GSK3β) and β-catenin. It regulates gene transcription by controlling the stability of β-catenin.
  2. Wnt-Calcium Pathway: This pathway is β-catenin-independent and leads to an increase in intracellular calcium levels. It activates protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), which will influence cell movement and signaling.
  3. Non-Canonical/Planar Cell Polarity (PCP) Pathway: This pathway is β-catenin-independent, and involves Disheveled (Dvl) activation, which then stimulates Rho and Rac which are two proteins responsible for cytoskeletal organization and cell polarity.

A pictural representation of the different pathways can be found in Figure 1 below.

Figure 1. The three main Wnt signaling pathways. (a) canonical Wnt signaling, (b) Wnt-calcium signaling, and (c) non-canonical Wnt/planar cell polarity signaling. 1

Each of these pathways plays a distinct role in cellular function, but it is the canonical Wnt pathway that is most often associated with schizophrenia. The two key components in this pathway are GSK3β and β-catenin.

Under normal conditions, active GSK3β promotes the degradation of β-catenin, decreasing its concentration in the cell which will result in inhibiting gene transcription. However, when GSK3β is inhibited, β-catenin remains stable and accumulates in the nucleus, where it activates Wnt target genes. Dysregulation of this process has been implicated in schizophrenia, suggesting that altered Wnt signaling may contribute to the disorder’s underlying neurobiological mechanisms.

Figure 2 give a good overall drawing of the many pathways of Wnt signaling.

Figure 2. A diagram that illustrates the pathways of Wnt signaling and how some medications alter this pathway.1

Here is an article that takes a deep dive into understanding the canonical Wnt pathway and how it might play a role in schizophrenia.

Medications and Their Effects on the Wnt Pathway

Since Wnt signaling plays a key role in brain development and synaptic plasticity, it is not surprising that some schizophrenia medications interact with this pathway. Two major classes of medications include lithium and dopamine D2 receptor antagonists (antipsychotics). These medications have been shown to influence Wnt signaling, particularly by affecting GSK3β and β-catenin levels.

Lithium is a mood stabilizer commonly used as a first-line treatment for bipolar disorder, but research suggests it may also provide therapeutic benefits for schizophrenia.1,2 Once inside the cell, lithium inhibits GSK3β, preventing it from degrading β-catenin. As a result, β-catenin accumulates, enters the nucleus, and promotes gene transcription. This mechanism is believed to contribute to lithium’s neuroprotective and mood-stabilizing effects, which may help improve symptoms in some individuals with schizophrenia.2

Traditional antipsychotic medications primarily work by blocking dopamine D2 receptors. This blockade prevents β-arrestin from inhibiting AKT, leading to AKT being active. Since AKT inhibits GSK3β, this cascade results in reduced GSK3β activity and an increase in β-catenin levels.1

Lithium’s Role in Treating Mood Disorders

Lithium has long been a key treatment for mood disorders, especially bipolar disorder. Additionally, research has highlighted its potential benefits for major depressive disorder (MDD).2 One of lithium’s most significant effects is its ability to reduce suicidal thoughts and behaviors, making it one of the few psychiatric medications known to have anti-suicidal properties.

Lithium helps modulate key neurotransmitters, including dopamine and serotonin. It is believed to reduce excessive dopamine activity, often linked to psychosis, while simultaneously increasing serotonin levels, contributing to its antidepressant effects.3 This dual action stabilizes mood and helps reinstate homeostasis.

Beyond neurotransmitter regulation, lithium is thought to enhance synaptic plasticity and strengthen neural connectivity.2Research indicates that lithium can strengthen connections in brain regions involved in emotion regulation, such as the prefrontal cortex and hippocampus. This neuroprotective effect has led researchers to explore lithium’s potential in treating neurodegenerative diseases like Alzheimer’s disease, due to its ability to support neuronal survival and cognitive function.

While lithium is primarily used for bipolar disorder, emerging research suggests it may also benefit individuals with schizophrenia, particularly those experiencing mood symptoms. Given that both schizophrenia and mood disorders involve dysregulated Wnt signaling and abnormal neural connectivity, lithium’s ability to modulate these pathways may help explain its therapeutic effects in both conditions.

Here is an article on how lithium can play a role in neuroplasticity and its potential for mood disorders.

Final Thoughts

While there are numerous medications available for schizophrenia, much remains to be learned about their mechanisms and optimal use. Lithium can significantly address many mood-related symptoms of the disorder, but it does not effectively target the psychiatric symptoms associated with schizophrenia. Therefore, combining lithium with antipsychotic medications is often a common strategy to support individuals with this condition.

However, antipsychotic medications come with their own set of concerns, including significant side effects. Combining two medications that influence major biological pathways may introduce additional complications. Continued research is essential, and it may eventually lead to the discovery of an ideal combination of treatments that can improve the quality of life for those affected by schizophrenia.

References

(1)      Singh, K. K. An Emerging Role for Wnt and GSK3 Signaling Pathways in Schizophrenia. Clin Genet 2013, 83 (6), 511–517. https://doi.org/10.1111/cge.12111.

(2)      Gray, J. D.; Mcewen, B. S. Lithium’s Role in Neural Plasticity and Its Implications for Mood Disorders. Acta Psychiatr Scand 2013, 128 (5), 347–361. https://doi.org/10.1111/acps.12139.

(3)      Pérez de Mendiola, X.; Hidalgo-Mazzei, D.; Vieta, E.; González-Pinto, A. Overview of Lithium’s Use: A Nationwide Survey. Int J Bipolar Disord 2021, 9 (1). https://doi.org/10.1186/s40345-020-00215-z.

 

Community/Health

It’s Not “Mental Illness” It’s Brain Health

Posted on by hdahlsei / 0 Comment

“Mental Illness”

Mental illness is often a scary phrase. It’s thought of in association with the words “disorder,” “sick,” or even worse, “crazy.” People often say “it’s all in your head.” Meaning a mental health diagnosis is somehow different, or less than any other physical health problem anywhere else in your body. Like it’s somehow your fault how your brain works, but not your fault how your heart, lungs, or kidneys work. 

It’s a taboo subject, and avoided at dinner parties at all costs. Yet it’s very common to ask people, kids even, if they’ve ever broken a bone. Then someone will regale everyone with a tale about the time they were goofing around and fell out of their tree fort, but showed up to school the next day and everyone signed their cast. We share when we have the flu like we’re talking about the weather. Yet if someone shares that they’re having a tough mental health day, the room falls silent. No one knows what to say. Which is quite funny when you think about it. Because we all have mental health. Everyone has a brain, so everyone has mental health. So maybe it’s far past time to start calling it “brain health,” or at least acting like it’s no different than physical health. 

Let’s take a look at schizophrenia…

We don’t really know exactly what causes it, but we do know it’s a neurodevelopmental disorder. This means there is something not working like it usually does in terms of brain development and neural connectivity. The Wnt signaling pathway is one of the key pathways associated with brain development, and has been found to play a role in schizophrenia [1]. 

  • Wnt and GSK signaling in schizophrenia [1].
    In people without schizophrenia, there is not enough GSK to phosphorylate β-catenin, an essential transcription factor. This means there is enough β-catenin to make it to the nucleus of the cell where gene transcription takes place that is essential to development[1].
  • However, in people with schizophrenia, there is generally less Wnt signaling activity, and more GSK activity. This increases the phosphorylation of β-catenin, and there is not enough to make it to the nucleus for gene transcription. An important piece of development is impacted [2]. This is connected to the dopaminergic system, which is overactive in schizophrenia. Dopamine plays a role in increasing GSK, which in turn decreases β-catenin and the resulting gene transcription process[3]. 

This is where the treatments come in… 

  • Antipsychotics are dopamine receptor antagonists, they reduce dopaminergic activity by targeting D2 receptors. This increases Akt, decreases GSK, and increases β-catenin [1].
  • Lithium starts by decreasing GSK, and increasing β-catenin [1].
  • Medications that target glutamate increase Akt, which decreases GSK, and increases β-catenin[1].

Genetics

Further evidence linking the Wnt pathway to schizophrenia is found in animal model genetic research. The DISC1 and Akt genes both reduce GSK activity, which results in the same pattern we’ve seen before [1].

  • ↓ Wnt & ↑ DA
  • ↓ Akt
  • ↑ GSK
  • ↓ β-catenin
  • ↓ gene transcription

Brain Health

Not everyone has a brain health diagnosis, just like not everyone has a physical health diagnosis. But there are some days we have to stay home from school or work because we’re sick with a cold or the flu. Because we are having a bad physical health day. The same can be said about having a bad brain health day. Just like an increase in germs impacts physical health, an increase in stressors impacts brain health. 

Artstract created by Hadlie Dahlseid

And some people do have a mental health, or brain health, diagnosis. Just like some people have a heart condition, asthma, or diabetes. Except with brain health, it’s treated like the person’s fault. Maybe we should look at the science that proves it’s “in your head” only in the literal sense. That proves it’s really all about your brain health, and not a moral failing or anything to do with the kind of person you are.

 

References

[1] Singh, K. (2013). An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clinical Genetics, 83(6), 511–517. https://doi.org/10.1111/cge.12111 

[2] Panaccione, I., Napoletano, F., Forte, A., Kotzalidis, G., Casale, A., Rapinesi, C., Brugnoli, C., Serata, D., Caccia, F., Cuomo, I., Ambrosi, E., Simonetti, A., Savoja, V., Chiara, L., Danese, E., Manfredi, G., Janiri, D., Motolese, M., Nicoletti, F., … Sani, G. (2013). Neurodevelopment in schizophrenia: The role of the Wnt Pathways. Current Neuropharmacology, 11(5), 535–558. https://doi.org/10.2174/1570159×113119990037 

[3] Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H.-G., Steiner, J., Bogerts, B., Braun, A. K., Jankowski, Z., Kumaritlake, J., Henneberg, M., & Gos, T. (2014). The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: Old Fashioned, but still in vogue. Frontiers in Psychiatry, 5(47). https://doi.org/10.3389/fpsyt.2014.00047

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A Genetic Pathway to Schizophrenia

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Artstract created by Charlene Geraci

Have you ever wondered if you are predisposed to a mental illness? Schizophrenia is thought to be a disorder of brain development and neural connectivity1, and genetic mutations may be a cause of such disruption. To understand how this is so though, let’s dive into a pathway that has shown promise in playing a critical role in schizophrenia: the Wnt signaling pathway.

 

Figure 1. This displays the canonical Wnt signaling pathway, beginning with the binding of a Wnt ligand to the LRPF6-Frizzled receptor and ending with either beta-catenin translocation into the nucleus or proteasomal degradation.1

 

The Wnt signaling pathway

The canonical/common Wnt signaling pathway is a highly conserved pathway, and when Wnt ligands aren’t binding to their receptors, a destruction complex containing glycogen synthase kinase 3 (GSK3) is active within the cell. Active GSK3 phosphorylates a protein called beta-catenin, which targets it for degradation by proteosomes. When Wnt ligands are present though, GSK3 is inactive, and this allows beta-catenin to be translocated from the cytoplasm into the nucleus. Here, beta-catenin binds to other cofactors to allow for transcription of genes. See Figure 1 for a visual representation of this pathway. When the transcription of Wnt genes is dysregulated, it can lead to changes that inhibit GSK3 and therefore increase beta-catenin levels, or the opposite.1

 

How BCL9 allows beta-catenin to perform its role in Wnt signaling

But how is that correlated with schizophrenia? Well, there is a type of genetic mutation called copy number variations (CNV) that involve duplications or deletions of genetic material, like DNA; and these CNVs have a high penetrance for schizophrenia if found in your DNA. In other works, although the risk for contracting these CNVs is low, they markedly increase risk of developing schizophrenia for those who have them.1

 

One CNV involves the B-cell lymphoma 9 (BCL9) gene, which stands out because it alters brain size and neural stem cell proliferation, which is tied with development of schizophrenia.1 It is notable because it regulates brain size by playing a critical function in Wnt signaling, as BCL9 is a transcriptional co-activator of beta-catenin2 that keeps beta-catenin within the nucleus and thereby helps to initiate gene transcription1. Seen in Figure 2 is the alpha-helical structure of BCL9 and the other co-activator of beta-catenin, which varies among animal-type.

 

Figure 2. This portrays the 3-dimensional structure of beta-catenin and its transcriptional co-activators, including BCL9.2

 

The BCL9 gene and how it impacts the Wnt signaling pathway in muscle growth

But BCL9 doesn’t just regulate brain size. For example, one study looked at the role of BCL9 is adult muscle stem cells. The researchers did this by silencing a section of the BCL9 gene that encoded for BCL9’s binding site for beta catenin. This generated mice that were null for BCL9/9-2 in muscle, and then this experimental group and the control group were subjected to a medium that contained Wnt3, analyzing for beta-catenin localization.3

 

Figure 3. Each graph in this figure compares the percentage of myogenic cells in WT versus BCL9/9-2 null mice. The higher percentage in the WT group that received Wnt3A contrasted with the unchanged percentage in the BCL9 null group indicates how proliferation of muscle cells cannot occur properly without BCL9 activity.3

 

Results, seen in Figure 3, showed that BCL9 is essential for Wnt signaling during specific stages of adult muscle stem cell activation because it promotes differentiation of adult myogenic progenitors. Figure 3 displays how myogenic cell levels were significantly decreased in mice who did not express the BCL9 binding site for beta-catenin, even in the presence of Wnt3, which is a glycoprotein of the Wnt family. Therefore, it is proven that BCL9 is needed for Wnt signaling to occur properly.3 For more in depth information on this intriguing study and its results, click here.

 

Mutations in the BCL9 gene & when they are connected to schizophrenia

So not only does the Wnt signaling pathway regulate brain size/neural stem cell proliferation, but it also regulates muscle growth. The pathway also regulates much more bodily processes, which will not be covered here, but to learn more, click here. These functions differ based off when and where during development the Wnt signaling pathway is occurring, but the common denominator that controls its expression is BCL9. Therefore, further research on BCL9’s specific role in different stages of development could help progress treatment of mental illnesses such as schizophrenia if researchers determine when the Wnt signaling pathway directs proper neural stem cell development. If mutations in the genes that direct Wnt signaling, such as the BCL9 CNV, can be identified early on in development, then perhaps pharmaceuticals that counteract the impact of such mutations can be administered to restore brain size and neuron growth, thus reducing manifestation of schizophrenia symptoms in those genetically predisposed. In addition, knowledge in this area could help further determine mechanisms useful in treating non-genetically inherited schizophrenia.

 

Footnotes:

1Michaud, Jacques L., Pourquié, Olivier. “An emerging role for Wnt and GSK3 signaling pathways in schizophrenia.” Clin Genet, vol. 83, pp. 515, doi: 10.1111/cge.12111

2Sampietro, James, et. al. “Crystal structure of a beta-catenin/BCL9/Tcf4 complex”. Mol Cell, vol. 24, no. 2, 2006, pp. 293-300, doi: 10.1016/j.molcel.2006.09.001.

2Brack, Andrew S., et. al. “BLC9 is an essential component of canonical Wnt signaling that mediates the differentiation of myogenic progenitors during muscle regeneration.” Dev Biol, vol. 335, no. 1, 2009, pp. 93-105, doi: 10.1016/j.ydbio.2009.08.014

 

Community/Disease/Health/Hot topics/Uncategorized

Dopamine – Have Researchers Found the Missing Piece to the Autism Puzzle?

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Imagine a world where you never know what the person next to you is thinking or how they’re feeling. Imagine attending social events or new experiences that are supposed to be exciting and fun but instead cause you debilitating stress and anxiety. Imagine being so overwhelmed and overstimulated by loud, bright, or crowded environments that you lose control of your body and begin to panic. Imagine the frustration, isolation, and confusion that these daily challenges would bring. For someone with autism spectrum disorder, they don’t need to imagine – this is their reality.

ASD: A “Puzzling” Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes problems with social communication and interaction, affecting about 1 in 36 children[1]. People with ASD often have restricted or repetitive behaviors or interests and may have abnormal patterns of movement. Autism can be diagnosed at any age, but it is described as a “developmental disorder” because symptoms usually emerge in the first two years of life[2]. Known as a spectrum disorder, there is a wide range of symptoms in people diagnosed with ASD. While autism is widely prevalent and the symptomology is generally understood, the exact cause of the disorder is unknown, and consequently, there is no cure for ASD. This is due to the heterogeneity of the disorder; many genetic and environmental risk factors likely contribute to a wide variety of symptoms. Recent research, however, may have unlocked a piece to the complex puzzle of ASD development and possible treatment directions. In this blog post, I will highlight the recent work on dopamine dysfunction in ASD, shedding light on what could be a successful avenue for improving the quality of life for those with ASD.

Dopamine: A Key Piece in the Neurochemical Puzzle

Often misunderstood as the brain’s “feel good” chemical, dopamine is a neurotransmitter that plays a crucial role in many bodily functions. Dopamine is essential for motivation and reward. It is released after completing something pleasurable like eating your favorite food, accomplishing a goal, or learning something new. Instead of making us “feel good” dopamine rather serves to reinforce these behaviors and motivates us to seek them out again. Dopamine is also essential for smooth and controlled movements, staying attentive and focused during tasks, and regulating mood[3]. So, what happens when dopamine doesn’t function the way it should? Dysregulation, or an imbalance of dopamine, can lead to symptoms like reduced motivation, mood swings, difficulty focusing, loss of reward, and movement disorders. It can also cause psychiatric and neurological disorders such as Parkinson’s disease, ADHD, depression, anxiety, and – you guessed it – autism spectrum disorder[4].

Piecing Together the Evidence: New Research on Dopamine Dysfunction in Autism

In the 2022 review article, “Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates”, DiCarlo and Wallace argue that one possible subtype of ASD may be associated with dopamine dysfunction[5]. The article proposes that dopamine dysfunction could contribute to ASD by disrupting key neural circuits involved in reward processing, social behavior, and motor control. As mentioned earlier, dopamine regulates motivation, attention, and the ability to process social and environmental cues, all of which are impaired in ASD. Specifically, dysregulation of dopaminergic signaling in the striatum and prefrontal cortex (brain regions essential for reward learning and decision-making, rich in dopaminergic neurons) may underlie the social communication deficits and repetitive behavioral characteristics of ASD. For example, reduced dopamine activity in the medial prefrontal cortex has been observed in individuals with ASD, which could impair their ability to assign value to social interactions, leading to social withdrawal.

[5] Dopamine pathways in the striatum and prefrontal cortex.

Additionally, abnormalities in dopamine transporter (DAT) function, such as altered dopamine reuptake or efflux, have been linked to hyperactivity and repetitive behaviors, which are common in ASD. Dopamine also modulates the balance between excitatory and inhibitory neurotransmission and helps to filter out neural “noise.” Disruptions in this balance are thought to contribute to the sensory sensitivities and neural hyperconnectivity seen in ASD. Finally, dopamine interacts with other neurotransmitter systems, such as glutamate and GABA, which are also implicated in ASD, suggesting that dopamine dysfunction may exacerbate broader neural circuit abnormalities[5]. Overall, dopamine dysregulation may play a central role in the neurobiological mechanisms underlying ASD.

[5] This illustration shows the synapse of a dopaminergic neuron. Released DA is cleared by DAT. Dopaminergic neurons modulate nearby Glu and GABA neurons.

The Missing Pieces

Dopamine dysfunction is undoubtedly an essential key to the puzzle of autism spectrum disorder, but many missing pieces remain regarding the exact mechanisms in which dopamine contributes to ASD. For example, it is still unknown whether dopamine abnormalities are a primary cause of ASD or a secondary effect of other genetic, neurobiological, or environmental factors[5]. The relationship between dopamine dysfunction and the heterogeneity of ASD is also not fully understood. Why do some individuals with ASD show hyperdopaminergic traits, such as hyperactivity, while others exhibit hypodopaminergic features, like social withdrawal? Finally, while some studies suggest that dopamine-targeted therapies may benefit certain individuals with ASD, it remains unknown how to identify which patients are most likely to respond to such treatments[5]. Addressing these gaps in knowledge is critical for developing more precise, dopamine-based treatments for ASD.

[6] This image shows fMRI differences in neurotypical and ASD females. fMRI could be used to map dopamine receptor availability and functional connectivity in individuals with ASD, aiding in biomarker development.

Solving the Puzzle

Dopamine dysfunction is implicated in autism spectrum disorder and is thought to contribute to symptoms like social deficits and repetitive behaviors, but the exact mechanisms remain poorly understood, therefore future research should focus on identifying biomarkers for dopamine-related ASD subtypes and developing targeted pharmacological therapies to improve outcomes for individuals with ASD. Hopefully, with these new discoveries and future research in this area, the pieces of the ASD puzzle will finally come together.

 

References

[1]           CDC, “Data and Statistics on Autism Spectrum Disorder,” Autism Spectrum Disorder (ASD). Accessed: Mar. 19, 2025. [Online]. Available: https://www.cdc.gov/autism/data-research/index.html

[2]           “Autism Spectrum Disorder – National Institute of Mental Health (NIMH).” Accessed: Mar. 19, 2025. [Online]. Available: https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd

[3]           “Dopamine: The pathway to pleasure – Harvard Health.” Accessed: Mar. 19, 2025. [Online]. Available: https://www.health.harvard.edu/mind-and-mood/dopamine-the-pathway-to-pleasure

[4]           H. Juárez Olguín, D. Calderón Guzmán, E. Hernández García, and G. Barragán Mejía, “The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress,” Oxid. Med. Cell. Longev., vol. 2016, p. 9730467, 2016, doi: 10.1155/2016/9730467.

[5]           “Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates – ScienceDirect.” Accessed: Mar. 20, 2025. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0149763421005650?via%3Dihub

[6]           “Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity | Translational Psychiatry.” Accessed: Mar. 20, 2025. [Online]. Available: https://www.nature.com/articles/s41398-020-0750-9

 

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The Female Brain’s Secret Shield: Understanding the Female Protective Effect in Autism

Posted on by Nessa Angau / 0 Comment

The female protective effect, explained | The Transmitter: Neuroscience News and Perspectives

The Mysterious Effect

Looking at this image you can see a woman holding a large umbrella, shielding her almost completely from the downpour. On the other side, you can see a man standing nearby, holding a smaller umbrella, leaving them more exposed to the rain. In this case, this image is representing how autism affects men and women differently.

Men with autism often experience the “rain” of symptoms more openly—they struggle socially, have clear repetitive behaviors, and are diagnosed earlier. Women, on the other hand, may have a natural protective “umbrella” that shields them from the most obvious signs of autism, making their struggles less visible. This concept is known as the Female Protective Effect (FPE), and it helps explain why fewer women are diagnosed with Autism Spectrum Disorder (ASD).

The Science

Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates - ScienceDirect
Figure. 1 Illustration of dopamine synaptic transmission, highlighting key genetic factors and molecular mechanisms implicated in autism spectrum disorder (ASD). [1]

According to research on dopamine dysfunction in ASD (DiCarlo & Wallace, 2022), autism is highly genetic, with over 1,000 genes linked to its development. Yet, for every three boys diagnosed with ASD, only one girl receives the same diagnosis. The FPE suggests that:

  • Females require a “higher genetic load” (more mutations or risk factors) to develop ASD.
  • Brain connectivity differs in males and females, affecting how ASD symptoms manifest.
  • Hormones, structural differences, or other biological factors may shield females from autism.

Interestingly, when females do develop ASD, their symptoms often look different from the classic signs seen in males. Instead of outwardly repetitive behaviors or social struggles, girls may mask their symptoms by copying social behaviors, leading to undiagnosis [1].

This masking can make it harder for clinicians to recognize ASD in females, as they may appear socially adept while still struggling internally with sensory sensitivities, rigid thinking, or intense special interests. Additionally, brain imaging studies suggest that female brains may have more compensatory neural pathways, allowing them to navigate social situations differently than males with ASD. [2]

Research also points to the role of hormones like estrogen, which may have a protective effect on brain development and dopamine regulation. Since dopamine dysfunction is a key factor in ASD, this could partially explain why males, who have different hormonal influences, are more frequently diagnosed. [3]

Hidden Storm

Think back to the umbrella analogy and let’s put the protective effect to a real life situation.

Maya and Jake grew up together, walking the same paths, attending the same schools, and facing the same world. But somehow, things always seemed harder for Jake. Loud noises made him cover his ears, unexpected plans threw him into meltdowns, and social interactions felt like an impossible puzzle. Maya, on the other hand, struggled too—but no one noticed.

She felt overwhelmed by bright lights and crowded hallways, but she smiled through it. She rehearsed conversations in her head, copying the way her classmates spoke, just to blend in. While Jake’s struggles were obvious, Maya’s were hidden beneath layers of practiced social scripts and forced eye contact. Teachers praised her for being quiet and well-behaved, while Jake was given extra support for his challenges.

The Female Protective Effect (FPE) is like an oversized umbrella in a storm—Maya had one, shielding her just enough that others didn’t see the rain. But that didn’t mean she wasn’t getting wet.

Why Understanding Dopamine and FPE Matters

Women in Autism - Autism Research Institute

Scientists are working hard to understand the Female Protective Effect and how it might lead to better autism diagnosis and treatment. Some key questions include:

  • What specific biological mechanisms protect the female brain?
  • How can we adjust diagnostic criteria to recognize ASD in women?
  • Could understanding FPE help create better interventions for both men and women?

Recognizing the role of dopamine dysfunction and the Female Protective Effect in autism diagnosis is critical for developing equitable and effective support systems. Medical professionals and educators can benefit from using gender-informed assessment tools that account for subtler signs of autism. Additionally, breaking down the stigma around autism and fostering greater acceptance can encourage more women and girls to seek evaluation and receive appropriate support.

By deepening our understanding of these neurological differences, we can move closer to a future where everyone, regardless of gender, receives the care and acknowledgment they deserve.

The goal isn’t just to acknowledge that women experience autism differently—it’s to make sure they get the recognition and support they need.

Resources

[1] DiCarlo, G. E., & Wallace, M. T. (2022). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience & Biobehavioral Reviews, 133, 104494. https://doi.org/10.1016/j.neubiorev.2021.12.017

[2] Ricemedia. (2023, June 27). What are the main signs of autism masking in women? Retrieved from The Autism Service website: https://www.theautismservice.co.uk/news/what-are-the-main-signs-of-autism-masking-in-women/

[3] Enriquez, K. D., Gupta, A. R., & Hoffman, E. J. (2021). Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder. Frontiers in Psychiatry, 12(12). https://doi.org/10.3389/fpsyt.2021.716673

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Understanding Dopamine Dysfunction in Autism: A New Window Into Personalized Treatment

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Autism Spectrum Disorder (ASD) is a condition many have heard of but may not fully understand. It is often thought of as a single condition but it is far from it. It’s a spectrum – characterized by social communication challenges, unique interests, repetitive behaviors, and sensory sensitivities. In the U.S., about 1 in 59 children are diagnosed with ASD. Underneath these symptoms lies immense biological diversity, which is where dopamine comes into the picture. [1]

What’s Dopamine Got to Do With Autism?

Dopamine is a chemical messenger your brain uses to signal when something is worth paying attention to – whether that’s a rewarding experience, an important task, or even a social interaction. [2]

When dopamine is working properly it helps us:

  • Feel pleasure from rewards
  • Stay focused
  • Decide what’s worth the effort

But when dopamine pathways are off, people can struggle with motivation, attention, and repetitive behaviors. [1]

Figure 1 [3]

Dopamine travels from key brain regions to areas that control movement, emotions, and thinking (Figure 1). Interestingly, issues pertaining to those brain regions – difficulty with motivation, repetitive actions, and social interaction – sound a lot like symptoms of autism. Could dopamine be one piece of the autism puzzle? [1]

What the Research Found

The article, Modeling Dopamine Dysfunction in Autism, looked at years of studies in people and animals. The authors found:

  • Brain scans show changes in dopamine-rich areas of the brain in people with ASD, especially in regions linked to habits and rewards.
  • The caudate nucleus, a brain area that helps manage repetitive behavior, is often larger in people with ASD (See Figure 2) – which might explain why many autistic people repeat actions or words.
  • These brain changes correlate with how severe a person’s repetitive behaviors are. In other words, the bigger the change, the more intense the behavior. [1]

Synaptic Dopamine Reuptake and Degradation - Neurotorium

Figure 2 [3]

Dopamine works at “synapses” – tiny gaps where brain cells pass messages. If dopamine isn’t balanced, the message can get distorted (Figure 2).

Why This Matters: Moving Toward Personalized Autism Treatment

Today, autism is mostly diagnosed by observing behavior. But imagine if we could also look at the brain’s biology, like dopamine function, to guide diagnosis and treatment.

If some people with autism have dopamine-related differences, they might respond better to specific treatments that target those pathways. For example, ADHD – often diagnosed alongside autism – involves dopamine imbalances too. ADHD treatments like stimulants that boost dopamine might help certain individuals on the spectrum if their brain chemistry fits.[1]

There’s even a connection to gut health – another common challenge for people with autism. The gut and brain communicate, and some gut bacteria produce dopamine-like chemicals. So, improving gut health might also impact dopamine-related behaviors. [1]

The Big Picture: The Future of Tailored Autism Care

The key takeaway? Autism isn’t a one-size-fits-all. Dopamine dysfunction is just one of many biological factors that could contribute to autism traits. By better understanding it, we open the door to:

  • Treatments tailored to an individual’s brain chemistry
  • Earlier, more accurate interventions based on brain scans or genetic tests
  • Fewer “trial-and-error” struggles with managing related conditions like ADHD or anxiety

This fits into a growing movement in mental health called precision medicine – treating people based on their unique biology, not just their symptoms (Figure 3).

What you need to know about Autism & Neurodiversity - The Autism Page

Figure 3 [5]

Looking Ahead

This research is a potential game-changer. It doesn’t claim that dopamine is the only cause of autism, but that it could be a crucial piece of the puzzle for some people. It shifts the conversation from what autism looks like to what’s causing it underneath. That shift could help millions of families get the targeted, effective care they deserve – sooner rather than later.

References

[1] DiCarlo, G. E., & Wallace, M. T. (2022). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and Biobehavioral Reviews, 133, 104494.

[2] Dopamine. healthdirect. (2023, October 17). https://www.healthdirect.gov.au/dopamine#:~:text=Dopamine%20acts%20on%20areas%20of,movement%20and%20other%20body%20functions.

[3] MT;, D. G. (n.d.). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and biobehavioral reviews. https://pubmed.ncbi.nlm.nih.gov/34906613/

[4] Synaptic dopamine reuptake and degradation. Neurotorium. (2024, May 13). https://neurotorium.org/image/synaptic-dopamine-reuptake-and-degradation-2/

[5] Admin. (2021, December 8). What you need to know about autism & neurodiversity. The Autism Page. https://www.theautismpage.com/autism-neurodiversity/

Health

Unraveling Dopamine Dysfunction in Autism Spectrum Disorder

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Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that affects millions of individuals worldwide. While ASD is primarily characterized by difficulties in social communication and repetitive behaviors, emerging research suggests that dopamine (DA) dysfunction may play a crucial role in some cases of the disorder.

Dopamine and Its Role in the Brain

Dopamine is a critical neurotransmitter involved in reward processing, motivation, learning, and motor control. It plays a key role in regulating social interactions, a core area of difficulty for individuals with ASD. Given its influence on behavior, researchers have long suspected that disruptions in the DA system may contribute to the symptoms observed in ASD. [1]

Key Findings on Dopamine Dysfunction in ASD

  • Altered DA Regulation: Studies show differences in DA levels and receptor activity in individuals with ASD, which may affect motivation and social behaviors.
  • Animal Models of ASD: Research using fruit flies, zebrafish, and rodents demonstrates that DA dysfunction leads to behaviors resembling those seen in ASD, such as social deficits and repetitive actions.
  • Neuroimaging Studies: MRI and PET scans reveal structural and functional differences in DA-rich areas of the brain, particularly the striatum, in individuals with ASD. [1]

Why This Matters

Understanding the role of dopamine in ASD could lead to more targeted treatments. If DA dysfunction is a key factor in some ASD subtypes, therapies that modulate DA signaling—such as medications or behavioral interventions—could help improve social engagement and reduce repetitive behaviors in affected individuals. Additionally, classifying ASD based on underlying neurobiological differences may lead to more personalized treatment approaches.

Looking Ahead

While the connection between DA and ASD is promising, further research is needed to fully understand how DA dysfunction interacts with genetic and environmental factors in ASD. Future studies may focus on refining animal models, developing DA-targeted therapies, and identifying biomarkers for DA-related ASD subtypes.

Final Thoughts

Research on dopamine dysfunction in ASD provides a better understanding of the neurobiological foundations of the disorder. By continuing to explore this link, scientists and clinicians can move toward a more nuanced understanding of ASD, ultimately leading to better, more effective treatments for individuals on the spectrum.

[1]
G. E. DiCarlo and M. T. Wallace, “Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates,” Neuroscience & Biobehavioral Reviews, vol. 133, p. 104494, Feb. 2022, doi: 10.1016/j.neubiorev.2021.12.017.
[2]
F. Zhao et al., “Oxytocin and serotonin in the modulation of neural function: Neurobiological underpinnings of autism-related behavior,” Front. Neurosci., vol. 16, p. 919890, Jul. 2022, doi: 10.3389/fnins.2022.919890.
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The Gut Microbiome and ASD

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Dopamine Dysfunction in Autism Spectrum Disorder

Understanding the complexities of Autism Spectrum Disorder (ASD) has led scientists to investigate potential causes, ranging from genetic factors to brain function. One area of research has focused on dopamine, a neurotransmitter critical for regulating mood, motivation, and motor control. But what if dopamine dysfunction isn’t just a result of brain abnormalities, but also influenced by factors outside the brain, like the gut microbiome? This is a question posed in the article Modeling Dopamine Dysfunction in Autism Spectrum Disorder: From Invertebrates to Vertebrates by Gabriella E. DiCarlo and Mark T. Wallace.

This article talks about the relationship between dopamine dysfunction and ASD, exploring how disruptions in dopamine pathways could contribute to the symptoms of ASD. They also talk about how a better understanding of these mechanisms (ranging from simple invertebrate models to more complex vertebrates) could open more thought for treatment. The research discussed in the article surrounds the importance of dopamine in neurodevelopmental disorders (particularly ASD) and reveals how both genetic and environmental factors interact to disrupt normal dopamine functioning.

Why is This Topic Still Being Explored?

Despite advances in research, the link between dopamine dysfunction and ASD remains a challenge in the scientific community. Autism Spectrum Disorder has a range of possible causes, including genetic, environmental, and neurobiological factors. One of the most debated areas of research is the role of dopamine. While dopamine dysfunction is known to be a large part of ASD, the exact details underlying this dysfunction are still not fully understood.

Consider the additional layer of research focused on the gut-brain connection, and there are more possibilities. Scientists have discovered that the gut microbiome might have a direct influence on brain function, including dopamine regulation [1]. This relationship, known as the “gut-brain axis,” is still relatively new in scientific research, and how imbalances in gut bacteria could lead to issues in dopamine synthesis or metabolism is only beginning to be understood.

The Link between Gut and Brain Health - Solabia Nutrition
The “Gut-Brain Axis”.

 

What Do We Know So Far?

In particular, animal models have been a big part of revealing the biochemical pathways that affect dopamine production and regulation. From invertebrates like fruit flies to vertebrates like mice and humans, scientists have identified consistent patterns of dopamine dysregulation in ASD [2].

The article highlights how the gut microbiome may play a role in dopamine regulation. It turns out that certain bacteria in the gut are capable of producing/influencing the production of L-DOPA, the immediate precursor to dopamine. This process might influence dopamine levels in the brain, suggesting that the gut microbiome could play a large role in neurological outcomes [2].

Research has shown that an imbalance in gut bacteria, known as dysbiosis, is common in individuals with ASD [1], and this might contribute to the dopamine dysfunction seen in these individuals. The influence of gut bacteria on dopamine synthesis, metabolism, and regulation opens up new possibilities for treatments that target not only the brain but also the microbiome.

Bacterial Colonization: Dopamine Synthesis and Metabolism

One of the most interesting parts of this research is the role of bacterial colonization in dopamine synthesis and metabolism. In a healthy gut, beneficial bacteria (commensal bacteria) support digestion and nutrient absorption and protect against pathogens. But disruptions to this microbial balance can lead to health issues, including gastrointestinal problems and neurological disorders [1]. In the context of ASD, research has found that dysbiosis can impact dopamine metabolism, potentially contributing to the behavioral and cognitive symptoms associated with ASD.

Certain strains of bacteria are capable of synthesizing L-DOPA, which is then converted into dopamine in the brain. This means that the gut microbiome could have an influence on dopamine levels, especially in the CNS. On the other hand, some gut bacteria can also metabolize dopamine into other compounds (like homovanillic acid) [3], which could affect dopamine levels and brain function. As research in this area grows, it suggests that addressing gut microbiome imbalances (whether through diet, probiotics, or other therapeutic interventions) could help dopamine regulation, possibly providing new treatment for ASD and other neurological conditions.

How Does This Affect Everyday Life?

Understanding that gut bacteria influences dopamine metabolism opens up new possibilities for therapeutic solutions that go beyond the traditional approaches. For example, dietary changes that promote the growth of beneficial bacteria in the gut could support dopamine production and help symptoms of ASD.

Diets rich in prebiotics could play a role in supporting a healthy microbiome. Foods like fruits, vegetables, and whole grains, which are high in fiber, may encourage the growth of bacteria that aid in dopamine synthesis. Similarly, fermented foods like yogurt and kimchi, which contain live beneficial bacteria, could directly impact gut health and potentially improve dopamine regulation. These affect the gut microbiome, potentially exacerbating dysbiosis and altering dopamine metabolism [3].

As a reminder, our health is interconnected in ways we might not fully understand. The gut-brain axis underscores the importance of taking a holistic approach to mental and neurological health, where diet, lifestyle, and microbiome health play a key role.

15 Prebiotic Foods for Gut Health - Stephanie Kay Nutrition
Food rich in prebiotics.

 

Calling for Action

The findings presented in the main article are a step forward in understanding the relationship between dopamine regulation and ASD. As researchers continue to explore the ways that gut bacteria influence brain function, new treatments could target the microbiome to restore normal dopamine production and improve outcomes for individuals with ASD. Gut microbiome may hold the key to understanding and potentially treating dopamine dysfunction in ASD. For researchers, this opens up new pathways for developing interventions that address both the brain and the gut. For parents, caregivers, and those living with ASD, it’s a reminder that our approach to treatment should be multifaceted, considering not only brain function but also the health of the gut. The next step would be to explore how we can use this knowledge to create therapies that improve dopamine regulation and overall health, ultimately helping those affected by ASD live better lives. The future of ASD treatment may be closer than we think, and the gut may be at the center of it all.

References
[1] Serra, D., Almeida, L. M., & Dinis, T. C. P. (2019). Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review. Neuroscience & Biobehavioral Reviews, 102, 290–298. https://doi-org.cordproxy.mnpals.net/10.1016/j.neubiorev.2019.05.010

[2] De Sales-Millán, A., Aguirre-Garrido, J. F., González-Cervantes, R. M., & Velázquez-Aragón, J. A. (2023). Microbiome–Gut–Mucosal–Immune–Brain Axis and Autism Spectrum Disorder (ASD): A Novel Proposal of the Role of the Gut Microbiome in ASD Aetiology. Behavioral Sciences (2076-328X), 13(7), 548. https://doi-org.cordproxy.mnpals.net/10.3390/bs13070548

[3] Heidari, H., & Lawrence, D. A. (2024). An integrative exploration of environmental stressors on the microbiome-gut-brain axis and immune mechanisms promoting neurological disorders. Journal of Toxicology & Environmental Health: Part B, 27(7), 233–263. https://doi-org.cordproxy.mnpals.net/10.1080/10937404.2024.2378406

[4] DiCarlo, G. E., & Wallace, M. T. (2022). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience & Biobehavioral Reviews, 133, N.PAG. https://doi-org.cordproxy.mnpals.net/10.1016/j.neubiorev.2021.12.017

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