A Genetic Pathway to Schizophrenia

Posted on March 24, 2025 by cgeraci / 0 Comment

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.³For 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

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

Posted on March 20, 2025 by Meg / 0 Comment

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 March 19, 2025 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

Posted on March 19, 2025 by ealslebe / 0 Comment

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]

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).

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

Posted on March 19, 2025 by jdeitz1 / 0 Comment

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

Posted on March 19, 2025 by rlannin1 / 0 Comment

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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OH NO! Comorbidity!

Posted on March 19, 2025 by jcopiske / 0 Comment

OH NO!- Comorbidity!

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that is known for its challenges in social situations such as social communication, repetitive behaviors, and problems with social cues. Those with ASD have difficulty expressing and understanding emotions, however this expands beyond the normal symptomology

Comorbidity is an additional disease on top of a primary diagnosis. They are more common in those with ASD than those without. Research shows a high rate of comorbidities- about 70% of those with ASD have co-occuring conditions that blur diagnosis and treatment for patients with ASD. Symptoms that develop with comorbidities add to the original symptoms of ASD making a healthy life difficult to have.

Genetic complexity

Autism does not have a single genetic cause. The developmental disorder is influenced by a multitude of factors. Primarily, multiple genetic factors like genetic mutations or copy number variations (CNVs). CNVs are a type of structural variation in the genome where DNA is deleted or duplicated. This changes normal function of genes and changes the number of gene copies present therefore, leading to developmental issues.

*Figure 1: Normal X chromosome compared to fragile X chromosome*

Fragile X Chromosome (FXS)

FXS is one condition that is associated with autism that is linked with DA dysfunction. It is the number 1 inherited cause of a wide range of intellectual disabilities. 1 in 3 individuals with ASD have FXS. This condition results from the repetition and mutation of the gene FMR1 which null mutants have significant increase in the synthesis of DA and 5-HT which is another name for serotonin- a neurotransmitter in charge of various functions including mood and helping out the nervous system.

In Figure 2, a typical chromosome the FMR1 gene will repeat just enough to maintain regulation for CGG repeat sequence, which will not interfere with functioning of the gene, however, a fragile X chromosome will exceed the number of regulated CGG repeat sequence and the FMR1 gene will slice, leaving an absence of the gene. Without the FMR1 gene neurons struggle to make synaptic connections in the brain.

*Figure 2: Typical mutation of genes versus full mutation present in fragile X syndrome*

When working with CNV’s you’re working with a lot of DNA! CNV’s make large changes to genetic material. This is one of the reasons why they are common in people who are neurodivergent. These genetic risk factors result in subtypes that ultimately have a cascade of behavioral symptoms. For example, deletion of specific gene like 16p11.2 can result in delayed speech and struggling with social intelligence. So rather than focus on one gene, like finding a needle in a haystack, its better to try and adapt and understand the subtypes and comorbities of ASD.

The Role of Dopamine and Dopamine Transporter DAT

Dopamine (DA) is a widely known neurotransmitter that influences an array of functions within the brain. As one of the top three numerous neurotransmitters found in the brain, dysfunction of this molecule can lead to neurodevelopemental and psychiatric disorders including Autism. Too much or too little dopamine in those with ASD cause symptoms such as issues with sensory processing, repetitive behaviors, motor control and social reward processing.

There are two primary dopamine receptors, D1 and D2. These receptors are critical for managing the effects that dopamine has on the brain. Dysfunction of these receptors has been proven to be linked in ASD. These two receptors contribute mainly to behavioral disruptions that are present in ASD such as, social deficits, behavioral flexibility, and cognitive attention.

D1 vs D2

D1 Receptors: During activation D1 receptors are primarily known for their synaptic plasticity, the strength in connection between neurons, and facilitating excitatory signaling, which is increasing neural activity. Synaptic plasticity and facilitating excitatory signaling regulates executive function and cognitive flexibility. They’re crucial for learning and memory. Dysfunction in D1 leads to deficits in communication and attention.

D2 Receptors: Unlike D1 receptors, D2 is mainly involved inhibitory signaling-which is the decrease of neural activity- and involvement with motor control and coordination, in ASD, an overactive reward system leads to repetitive behaviors. In this situation the brains reward pathways are eing hyperstimulated and overly sensitive. When D2 receptors are not functioning there is no ‘manager’ to modulate motor control and coordination within movements.

DAT is the dopamine transporter in charge of regulating dopamine. The process in which dopamine levels are regulated from the synapse back into the neuron This means a dysfunction in DAT is a dysfunction in dopamine signaling. DA signaling drives behavioral activation which increases with reward rate.

What does This Have to do With Comorbidities?

ASD and its comorbid conditions can help research within dopamine receptors to understand where dysregulation occurs. ASD contributes to neurological development of existing disorders as behavior, cognition, and emotion are all affected. Comorbidities are harmful to an individuals quality of life as with autism, it can be difficult to express how you are feeling. If we evaluate dopaminergic dysfunction we can understand core symptomology and be closer to the answer.

Al-Beltagi M. (2021). Autism medical comorbidities. World journal of clinical pediatrics, 10(3), 15–28. https://doi.org/10.5409/wjcp.v10.i3.15

DiCarlo, G. E., & Wallace, M. T. (2022, February). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and biobehavioral reviews. https://pmc.ncbi.nlm.nih.gov/articles/PMC8792250/

Hunter, J. E. (2024, May 16). FMR1 disorders. GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK1384/

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Autism and the Gut-Brain connection

Posted on March 18, 2025 by ttiongso / 0 Comment

What is Autism?

Autism Spectrum Disorder is a developmental condition that affects an individual’s cognitive, social, and emotional functioning[1]. It is a spectrum, meaning that its symptoms and severity vary widely among individuals. While some individuals may have significant impairments in social interactions, others may demonstrate only mild deficits. The spectrum nature of autism means that no two people with autism experience the same set of challenges or strengths. Autism is not a disease but rather a neurodevelopmental condition that typically appears in early childhood. It is diagnosed more often in boys than in girls, with current estimates suggesting that 1 in 36 children and 1 in 45 adults are affected by the disorder[2].

Autism can be diagnosed at various ages, but most individuals are diagnosed around the age of 5, even though signs may be present as early as age 2[2]. Diagnosing autism early can help in providing the necessary support and interventions that can assist in improving long-term outcomes. Furthermore, autism often co-occurs with other psychiatric and medical conditions, a phenomenon known as comorbidity[2]. Common comorbidities include Attention-Deficit/Hyperactivity Disorder, anxiety disorders, depression, gastrointestinal issues, seizures, and sleep disorders[2]. Understanding these co-occurring conditions is crucial for providing comprehensive care for individuals with autism. Other sources on Autism symptoms and care can be found here.

Symptoms

Symptoms of autism involve deficits in social communication and interactions and restrictive or repetitive behaviors or interests[1].

Lack of facial expressions (by 9 months )
Delayed language skills
Delayed movement skills
Avoiding eye contact
Lack of social gestures ( shaking hands or waving goodbye by 12 months old)
Disinterest in social interaction (by 24 months old)
Difficulties identifying others’ emotions
Obsessive interests
Strong negative emotional response in response to minor changes
Excessive repeating of words or phrases
Strong reaction to certain sensory stimuli
Dependance on strong routines

The Gut- Brain Connection

Research on mice that lack gut microbiota showed that these animals display altered social behaviors and increased anxiety-like traits[3]. This suggests that gut bacteria contribute to brain function and behavior, and these interactions can be seen in Figure 1. Additionally, gut microbiota influence neurotransmitter systems, including dopamine and serotonin, both of which play critical roles in ASD-related symptoms[3].

The Enteric nervous system regulates gut function and shares neurotransmitters and signaling pathways with the central nervous system. Dysregulation of these pathways has been observed in Autism, supporting the idea that gut dysfunction may be linked to behavioral and neurological symptoms[3]. Studies have also found differences in the expression of synaptic proteins in Autism models, reinforcing the potential impact of gut microbiota on brain development and function[3].

Conclusion

In conclusion, autism is a complex and multifaceted disorder that requires a personalized and holistic approach to diagnosis and treatment. Ongoing research into the gut-brain connection may eventually uncover new strategies to improve the quality of life for individuals on the autism spectrum.

[1] Centers for Disease Control and Prevention. (2024, November 25). About autism spectrum disorder. Centers for Disease Control and Prevention. https://www.cdc.gov/autism/about/index.html

[2] Autism spectrum disorder (ASD). Autism Speaks. (2025). https://www.autismspeaks.org/what-autism

[3]DiCarlo, G. E., & Wallace, M. T. (2022, February). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and biobehavioral reviews. https://pmc.ncbi.nlm.nih.gov/articles/PMC8792250/

[4]Liu, L., Huh, J., & Shah, K. (2022, March). Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS. EBioMedicine. https://pubmed.ncbi.nlm.nih.gov/35255456/

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Fragile X Syndrome and its ties to Autism

Posted on March 18, 2025 by klind2 / 0 Comment

Artstract created by Ren Lind

There are many different theories as to the causes of Autism, however, Fragile X Syndrome is a direct cause for an estimated 2-6% of Autism cases. [1] Theories for other causes include genetics, environmental factors, the communication between neurons being disrupted, and others, but today we’ll be focusing on Fragile X.

Fragile X Background

Fragile X Syndrome (FXS) is an inherited genetic disorder. It gets its name from the X chromosome appearing “fragile” compared to a typical X chromosome, as figure 1 depicts.

Figure 1: A mutation in the FMR1 gene leaves a gap in the X chromosome [2]

Since it’s on the X chromosome, males with XY chromosomes will always have FXS if inherited, while females with XX chromosomes can be carriers for FXS if it’s only on one X chromosome. Typically, males will have more severe symptoms compared to females. [3]

FXS individuals have a mutation on the FMR1 gene. This gene is responsible for making a protein that manages and develops synapses between neurons. Synapses are where communication between neurons gets passed along and important messages can be spread to the brain, or the body so bodily processes can happen.

This gene mutation can lead to behavioral and social challenges, intellectual deficits, alterations in physical features, anxiety, and delayed speech and learning in childhood, among other symptoms. Typically, FXS is diagnosed between 12 months and 3.5 years old, but it can be diagnosed later in life. Symptoms of FXS greatly overlap with symptoms presented in Autism Spectrum Disorder.

Autism Background

Autism Spectrum Disorder (ASD) is characterized by social deficits and repetitive motions or interests throughout life. [4] Symptoms such as social anxiety, avoiding eye contact, social impairment, and other diagnostic symptoms overlap between FXS and ASD.

FXS causes Autism because the symptoms presented can be the same, depending on which symptoms the individual with FXS displays. It’s important to note that not all people with FXS will be diagnosed with ASD because they may have different symptoms than those of Autism. However, about 60% of males with FXS have Autism, and 20% of females with FXS have Autism. [5]

ADHD and Seizures Co-occurring

Interestingly, there are also comorbidities of Attention-Deficit/Hyperactivity Disorder (ADHD) and seizure for people with Fragile X and Autism. Around 50% of people with Fragile X and ASD also have ADHD. [6]

Figure 2: Overlap between ADHD, Autism, and Fragile X Syndrome [7]

Seizures are a known comorbidity of ASD, [8] but around 15-20% of people with Fragile X also have seizures. A literature article written by Dicarlo and Wallace hypothesizes that ADHD and seizures may have similar biological pathologies to Autism, however, more research is needed to understand why these conditions seem to travel together.

Summary

Autism has many theorized causes and risk factors, but Fragile X Syndrome is a confirmed cause for a small percentage of Autism cases. This occurs because Fragile X can present the same way as Autism, creating an overlap between the conditions, however, not every person with Fragile X will have the same symptoms as Autism.

Resources

[1] Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., Saldarriaga, W., Duan, X., & Hagerman, R. (2017). Fragile X syndrome and fragile X-associated disorders. F1000Research, 6, 2112. https://doi.org/10.12688/f1000research.11885.1

[2] Image from https://healthjade.net/fragile-x-syndrome/

[3] Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., Saldarriaga, W., Duan, X., & Hagerman, R. (2017). Fragile X syndrome and fragile X-associated disorders. F1000Research, 6, 2112. https://doi.org/10.12688/f1000research.11885.1

[4] Dicarlo, G., Wallace, M. (2022). Modeling dopamine disfunction in autism spectrum disorder: from invertebrates and vertebrates. Neuroscience and Biobehavioral Reviews, 133. https://doi.org/10.1016/j.neubiorev.2021.12.017

[5, 6, 7] Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., Saldarriaga, W., Duan, X., & Hagerman, R. (2017). Fragile X syndrome and fragile X-associated disorders. F1000Research, 6, 2112. https://doi.org/10.12688/f1000research.11885.1

[8] Dicarlo, G., Wallace, M. (2022). Modeling dopamine disfunction in autism spectrum disorder: from invertebrates and vertebrates. Neuroscience and Biobehavioral Reviews, 133. https://doi.org/10.1016/j.neubiorev.2021.12.017

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How Genetic Epilepsies Relate to Autism Spectrum Disorder Symptoms

Posted on March 18, 2025 by cgeraci / 0 Comment

Introduction

Could epilepsy and autism be caused by your genes? Epilepsy is a common disorder that accompanies autism spectrum disorder (ASD), and ASD has been linked with multiple random genetic mutations in the DNA that comprises various genes.¹ While genetics is not the only cause of ASD, the question of what mutated genes cause the epileptic seizures in many people with ASD can be asked.

To start off, most epilepsies are a combination of environmental and genetic factors, with genetic epilepsies only making up a small portion of epilepsies. With those that are genetic though, called idiopathic epilepsies, there are various mechanisms that initiate the process by which someone with a normal brain becomes susceptible to developing epilepsy (epileptogenesis). Those mechanisms include ion-channel disorders, the mechanisms underlying progressive myoclonus epilepsies (“myoclonus” meaning causing involuntary muscle spasms), developmental abnormalities, energy metabolism defects, and neuronal migration disorders.²

Table 1. This table displays idiopathic epileptic syndromes, their associated genes, which chromsomes these genes are on, and the mode of inheritance by which these genes are passed on. Oligogen refers to how the trait is influenced by a few genes.²

As you can see in Table 1, there are many epileptic syndromes linked to various genes on different chromosomes, and the way these syndromes are inherited varies. Clearly, genetics plays a role in epilepsy, but how does that correlate to ASD?

ASD Theories

To determine this, we must look at what the impacted genes do within the body and determine parallels between these results and the symptomatic characteristics of ASD. One theory regarding the cause of ASD is the excitatory-inhibitory (E/I) balance disruption theory, which proposes that ASD is due to alterations in the ratio of excitatory to inhibitory neurotransmission. This theory would explain the hyperactivity/hyperexcitability and reduced ability to maintain attention found in ASD patients. Another theory is the altered network connectivity theory, which hypothesizes that changes in neuronal connections within the brain are the main drivers of behaviors observed in ASD.¹

Genes Related to Epilepsy & How They Correlate to ASD

Looking at Table 1 again, we see the epileptic syndrome abbreviated as ADNFLE. This is caused by mutations in the CHRNA4 or CHRNB2 genes located on chromosome 20. These genes typically encode for the alpha and beta subunits of nicotinic acetylcholine receptors, which are ion channels. When ADNFLE occurs, the wall of this ion channel is disrupted, disrupting cholinergic system function.² The system plays a large role in memory, attention, and neuronal connectivity, so this epileptic syndrome, if co-occurring with ASD, could perhaps explain the working memory deficits seen in ASD and ties in well with the altered network connectivity theory of ASD.

Below ADNFLE on Table 1 we see BFNC, which is an ASD-inherited seizure disorder that causes mutations in voltage-gated K+ channel genes KCNQ2 and KCNQ3. In this disorder, the structure of a K+ channel pore is disrupted, reducing potassium current, which as can be seen in Figure 1, is a powerful controller of neuronal firing by controlling repolarization of the neuron.³ If K+ current is reduced, a neuron cannot return to its resting membrane potential, and this causes increased excitability of neurons since there are more easily brought to the threshold potential that causes an action potential to be sent.²Thus, BFNC ties in nicely with the E/I balance disruption theory of autism and shows how epileptic disorders commonly cause the epileptic symptoms characteristic to ASD.

Figure 1. This diagram shows the flow of ions as an action potential is initiated during depolarization and is subsided during repolarization.³

There are other epileptic syndromes associated with genetic mutations that have similar impacts on ion channels, disrupting neuronal excitability, as well as other mutations related to disruptions of neuronal connectivity. For more examples of these genetic mutations and those that cause the earlier mechanisms characteristic to idiopathic epilepsies, click here.

In conclusion, idiopathic epilepsies are caused by various mechanisms, but the ones that correlate most with ASD are those that disrupt neuronal excitability and/or neuronal connectivity. Therefore, further research should be done to determine if medications that target these processes can improve the symptoms of epileptic phenotypes of ASD.

Footnotes

¹Maximilians, Ludwig. “Genetics and epilepsy.” Dialogues Clin Neurosci, vol. 10, no. 1, 2008, pp. 29-36, doi:10.31887/DCNS.2008.10.1/oksteinlein

²DiCarlo, Gabriella E., Wallace, Mark T. “Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates.” Neurosci and Biobehavioral Reviews, vol. 133, 2022, pp. 1-11, https://doi.org/10.1016/j.neubiorev.2021.12.017

³Changes in Sodium and Potassium Conductances. Cellular Physiology. https://neurotext.library.stonybrook.edu/C4/C4_5/C4_5.html