The article we have covered in a previous week, “An emerging role for Wnt and GSK3 signaling pathways in schizophrenia” by Jacques L. Michaud was an article about the basics on schizophrenia disorder and how it may be connected to Wnt (pronounced “went”) and GSK3 pathways. Basically, it works as following; we commonly think of schizophrenia as a disorder in perception and many other domains throughout common society. However, the article points out a fascinating new and notable consistent pattern where Wnt and GSK are decreased and increased in the body respectively within a case of schizophrenia.^1 The topic today is why people should care about this topic and what the people must know, so without further ado let’s get reading!
The article informs us that some of the distinguishable characteristics of schizophrenia disorder are connected to Wnt and GSK. Though, the article specifically focuses mainly on how poking at these two pathways are done to treat schizophrenia. As a result of this connection, we can now classify an immeasurably correlation here.
Figure two from the article mentioned above is especially excellent at explaining this where it was needed (excellently timed, or in other words placed well). That piece is simultaneously even a diagram which shows even a seemingly full diagram of the Wnt pathway used in pharmaceutical intervention. Although, one slight problem could be that it could feel a tad bit overwhelming if you’re not too familiar with the applied terms of figure two in the Neuroscience field. This was an excellent piece to me for it is maximized simplicity because, for clear reasons, that kind of thing strongly helps. The figure may also benefit people uninvolved in Neuroscience as well because figure two works similarly like speech bubbles in comic books with all the brief, yet descriptive, labeling, and I find that effective myself in general because it’s easy on the eyes to track or logicate.
Now, at this point, one, such as yourself, may wonder why people really should care about all the above information. Well, let’s answer with essential basics to answer ourselves by quickly asking ourselves something simpler first; what really is schizophrenia disorder? Well, schizophrenia is not the nicest experience one can have. According to Mayo Clinic, schizophrenia is known to be a, “serious mental health condition that affects how people think, feel and behave”^2 that in some cases can turn into medical emergencies (suicide attempts, concernable behavior, or inaccessiblities to core needs. Considering that we know that our core senses to be most essential, it’s no shock to pretty much anyone that such a scenario can turn serious fast. Let us put this into perspective with some real world folks.
Lionel Aldridge, for example, experienced symptoms along the lines of paranoia, irritation, social struggles. In life, he was a sport athlete with a winner of 3 world sports championships and many NFL games throughout his career as defense. He experienced a myriad of challenges partly due to schizophrenia such as his journey to recovery from the disease (which was a success), homelessness where he lost a superbowl ring during, etc.
Sources:
1: An emerging role for Wnt and GSK3 signaling pathways in schizophrenia” by Jacques L. Michaud
2: https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443
From Wnt to Wonder → The Neuroscience Behind Schizophrenia
Schizophrenia is a complex and misunderstood disorder that affects emotional and physical behavior. Even though this disorder affects millions, it remains a poorly understood developmental disorder. The stigma that co-occurs with Schizophrenia leads to oversimplified symptomology.
However, emerging research reveals Schizophrenia is strongly linked to the Wnt pathway, which is a network of proteins that work together in brain developement, communications, and homeostasis. Research suggests that dysregulation of the Wnt pathway could be the root of Schizophrenia, leading to the importance of understanding what Schizophrenia is and how it manifests.
What is Schizophrenia?
This disorder is multifaceted; affecting thought processes, emotions, and behaviors. There are many misunderstandings and stigmas surrounding Schizophrenia. Characteristics in symptomology lead to discrimmination which overshadows the biological and developmental beginnings of the disorder.
There are five different subtypes of Schizophrenia. The symptoms for each subtype vary, and understanding these subtypes could be helpful in recognizing the symptomology and how it connects to the biology beneath the surface.
Paranoid: Most common form: consists of hallucinations and/or delusions, speech and emotions may not be affected, develops later in life.
Fig. 1 Subtypes of Schizophrenia
Disorganized/Hebephrenic: Develops 15-25 years, disorganized behavior, and thoughts, short lasting hallucinations/delusions, may have diagnosed speech patterns and others may find it difficult to understand you.
Catatonic: Move from being very active to very still, may not talk much, can mimic others speech and movement.
4. Undifferentiated– some signs of each
5. Residual -history of psychosis, only negative symptoms, slow movement, poor memory, lack of concentration, and poor hygiene
What is the Wnt Pathway?
One pathway has emerged as a critical path in Schizophrenia: the Wnt pathway. This is a network of proteins that communicate signals through cellular processes and facilitate regulation and communication throughout the brain. Methods have uncovered that dysregulation of the Wnt pathway is linked to multiple developmental disorders, contributing to cognitive deficits, structural brain changes, and symptomology. Structural brain changes cause alterations in neural connectivity that contribute to cognitive deficits and emotional dysregulation.
The Wnt pathway is used in a range of biological processes such as cell development, homeostasis, and differentiation which is why the pathway is so critical in psychiatric disorders. All processes stimulate each other, the Wnt pathway can be evalutated to understand why symptoms occur in Schizophrenia and ways to prevent them.
Think of the Wnt pathway as a series of relay runners passing a baton (signals) to regulate brain processes. When something disrupts the relay, its like dropping the baton- leading to the changes, neurological and behavioral, that we see associated with Schizophrenia.
The Science of the Wnt Pathway
The Wnt pathway is essentially a network of Wnt proteins, which are a family of secreted glycoproteins that bind to receptors on the surface of cells which in turn initiates a cascade of signaling events. Frizzled (Fz) receptors are the primary receptors for Wnt proteins. When Wnt binds to Fz receptors, intracellular signaling cascades are activated and trigger various cellular responses. Two pathways that can be trigged are a canonical pathway and a noncanonical pathway. Beta catenin is involved when a canonical pathway is trigged by an intracellular signaling cascade. On the other hand, when a noncanonical pathway is triggered, beta catenin is not involved in the process.
Fig. 2 Causation for psychotic symptoms; processes stimulate one another
How it works: Beta Catenin
β-Catenin is a central component of the canonical Wnt signaling pathway, which regulates a wide variety of cellular processes such as cell differentiation, proliferation, migration, and synaptic plasticity. It acts as a transcriptional co-activator that, in the presence of Wnt signaling, translocates to the nucleus and binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to initiate gene expression.
Altered β-catenin signaling during critical periods of brain development, especially in the formation and maintenance of neural circuits, may contribute to cognitive deficits and impaired synaptic plasticity seen in Schizophrenia. β-Catenin’s role in regulating synaptic function might be disrupted in individuals with Schizophrenia, affecting neuronal connectivity and circuit formation.
Two Important Pathways
The Wnt pathway is critical for optimal brain health. By understanding the relationship between the Wnt pathway and Schizophrenia we can see a potential future of treatment possibilities. Research proposes that interventions of the Wnt pathway could improve life quality for those with Schizophrenia.
Fig 3. When the Wnt pathway is in charge of self renewal, differentiation, microenvironment, quiescence, senescence, and cancer stem cells
Canonical
The canonical pathway produces beta catenin. This pathway is initiated when Wnt ligands bind to receptors on the cell membrane, primarily a Fz family receptor with low-density lipoprotein receptor-related proteins. The pairing of these two molecules sets off a chain reaction inside the cell.
Without Wnt signaling (when it’s turned off), beta catenin is broken down by the destruction complex, which is a group of proteins involving, GSK3β, Axin, APC, and CK1α. This group of proteins stays assembled when Wnt signaling is off. If Wnt ligands are binding to their receptors (Wnt signaling is on) the complex is disassembled. Therefore, beta catenin is accumulated in the cytoplasm and moves to the cell nucleus. Beta catenin then has the ability to interact with co-factors like TCF/LEF to initiate the transcription of Wnt-dependent target genes.
Fig. 4 Comparison of Wnt signaling off/on
Noncanonical
Does not involve β-catenin-mediated transcription
Two pathways are the planar cell polarity (PCP) and Wnt/calcium pathways
PCP signaling involves Wnt signaling through Fz receptors and G proteins
Rho and Rac proteins are activated to regulate the cytoskeleton
The Wnt/calcium pathway is triggered by Fz activation
Increases intracellular Ca2+ levels
Leads to the activation of protein kinase C (PKC), affecting a broad range of cellular functions
Particularly in the central nervous system (CNS) which influences neural circuit formation and synaptic plasticity
Fig. 5 A Wnt responsive cell in a canonical pathway versus a noncanonical pathway
What’s the big whoop?
Schizophrenia is a complex psychiatric disorder with significant neurodevelopmental and genetic groundwork. By understanding the inner-workings of Wnt signaling, research can open new innovative therapies that potentially could change the lives of individuals with Schizophrenia.
Recent research has highlighted the critical role of the Wnt signaling pathway, particularly β-catenin, in the development and progression of Schizophrenia. β-Catenin is a key player in the canonical Wnt pathway.
β-Catenin and the Wnt signaling pathway play a significant role in brain development, synaptic function, and cognitive processes. Dysregulation of this pathway, particularly through altered β-catenin signaling, is emerging as an important factor in the development of Schizophrenia. As research continues, understanding the precise role of β-catenin could open new doors for targeted therapies, offering hope for better treatment strategies for this complex and debilitating disorder.
By exploring the intersection of genetic, molecular, and pharmacological factors in Wnt signaling, we move closer to understanding the biological basis of Schizophrenia and developing more effective treatments.
References
KK;, S. (n.d.). An emerging role for Wnt and GSK3 signaling pathways in Schizophrenia. Clinical genetics. https://pubmed.ncbi.nlm.nih.gov/23379509/
Imagine your brain as a bustling city. Neurons are the citizens, busily transmitting signals and information. To keep the city running smoothly, there’s a complex network of roads and traffic lights—this is your Wnt signaling pathway. Now, meet Akt, the traffic controller who makes sure everything flows without chaos.
What is Akt, and Why Should You Care?
Akt, short for protein kinase B (PKB), is like a supervisor in your brain. It manages cell growth, survival, and even how cells talk to one another. But one of its most fascinating jobs is regulating the Wnt signaling pathway, which controls how neurons grow and connect. When the system works well, it’s like green lights at every intersection. When it doesn’t, things get jammed up—and that can contribute to brain disorders like schizophrenia.
How Akt and Wnt Work Together
According to research on in the canonical Wnt pathway in schizophrenia (the main road in our city analogy), a protein called GSK3β is like a demolition crew. It breaks down a protein named β-catenin, which is essential for turning on brain-friendly genes [1]. But here’s where Akt steps in: it hits the brakes on GSK3β, preventing it from destroying too much β-catenin. This means those beneficial genes can activate, supporting brain development and maintenance.
Lithium, a medication often used to treat mood disorders, also stops GSK3β. But research suggests lithium works best when Akt is already on the job. Without Akt’s help, lithium’s effect would be like a malfunctioning traffic light—not as effective [2].
When Things Go Wrong
Figure 1. The signaling pathway of Akt in schizophrenia [1]
In schizophrenia, Akt sometimes goes offline, leaving GSK3β unchecked (Singh, 2013). This means less β-catenin reaches its destination, leading to problems in brain connectivity and communication. Think of it like broken traffic signals causing congestion and confusion.
This disruption doesn’t just impact thinking and memory; it also affects emotional regulation and perception. Low Akt activity may contribute to the hallucinations, delusions, and cognitive deficits that characterize schizophrenia. Research has also shown reduced Akt1 expression in the brains of people with schizophrenia, further underscoring its importance [3].
Moreover, genetic mutationsor variations that reduce Akt’s effectiveness can make individuals more susceptible to developing schizophrenia. In some cases, environmental factors like stress or substance abuse can further impair Akt signaling.
Fortunately, some antipsychotic medications give Akt a boost. By restoring its activity, they help get Wnt signaling back on track, reducing symptoms and improving cognitive function. Lithium, for example, indirectly enhances Akt function by inhibiting GSK3β, providing a double layer of protection against disrupted Wnt signaling.
Emerging research is also exploring the use of Akt activators or other drugs that directly target this pathway. These new approaches could offer more effective treatment options with fewer side effects in the future.
The Potential of Akt-Targeted Therapies
Figure 2. Diagram showing targeting on PI3K/AKT Pathway for cancer therapy [4]
While Akt’s role in schizophrenia is well-studied, its influence extends to other neurological and psychiatric disorders. Dysregulation of the Akt pathway has been linked to bipolar disorder, depression, and even Alzheimer’s disease. Researchers are investigating how therapies that target Akt could help manage these conditions by restoring proper signaling pathways.
Studying Akt in animal models and human stem cell systems is also helping scientists understand how it influences brain function. Advanced imaging and molecular techniques are providing new insights into how Akt and Wnt signaling networks operate in real-time. This research is essential for developing better interventions for brain health.
Final Thoughts
Akt may not be a household name, but its influence in your brain is undeniable. From preventing neurological roadblocks to ensuring essential signals get through, it’s the ultimate traffic controller of your mental metropolis. Understanding and supporting Akt’s function could open doors to better treatments for brain disorders in the future.
Moreover, lifestyle factors like regular exercise, a balanced diet, and stress management may support healthy Akt function. Maintaining overall brain health can be a proactive way to ensure this critical signaling pathway remains balanced.
As science advances, personalized medicine approaches are expected to further refine Akt-targeted therapies. By tailoring treatments to individual genetic and biochemical profiles, healthcare providers may achieve more effective and lasting outcomes.
Next time you hear about brain health, remember to thank Akt—your brain’s reliable traffic marshal!
Resources:
[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] Chokhawala, K., Saadabadi, A., & Lee, S. (2024, January 14). Lithium. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK519062/
[3] Chang, C.-Y., Chen, Y.-W., Wang, T.-W., & Lai, W.-S. (2016). Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions. Scientific Reports, 6(1). https://doi.org/10.1038/srep33095
[4] He, Y., Sun, M. M., Zhang, G. G., Yang, J., Chen, K. S., Xu, W. W., & Li, B. (2021). Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduction and Targeted Therapy, 6(1), 1–17. https://doi.org/10.1038/s41392-021-00828-5
Why Cannabinoid Receptors in the Brain Matter More Than You Think
The brain is an intricate network of neurons and chemical signals, constantly adapting and responding to the world around us. But did you know that the brain has its own cannabis-like system? Scientists have discovered that the endocannabinoid system (ECS) plays a crucial role in regulating mood, memory, pain, and even neuroprotection. However, despite its importance, many people remain unaware of how this system functions and its potential impact on human health.
Our understanding of the ECS has grown tremendously, and researchers now recognize that its dysfunction is linked to various neurological conditions. Scientists have found that cannabinoid receptors, particularly CB1 and CB2, are essential in modulating brain activity and protecting against neurodegeneration. But there’s still much to learn, and unlocking the full potential of this system could revolutionize medicine.
Therefore, by studying cannabinoid receptors, we may uncover groundbreaking treatments for conditions such as Alzheimer’s, multiple sclerosis, and traumatic brain injuries. The future of neuroscience and medicine may lie in harnessing the power of cannabinoids, making this an area of research that deserves our attention.
The Science Behind Cannabinoid Receptors
The article “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease” explores how CB1 and CB2 receptors influence brain function and disease[1]. CB1 receptors are abundant in the brain, particularly in regions associated with cognition, movement, and emotion, such as the hippocampus, neocortex, and basal ganglia. They regulate neurotransmitter release, affecting everything from anxiety to learning ability. Meanwhile, CB2 receptors, though primarily found in immune cells, have been discovered in the brain as well, where they play a role in inflammation and neuroprotection[2].
Figure 1. This figure highlights the pathways activated by cannabinoid receptors, showing how they modulate synaptic plasticity and neuronal signaling[3].
What Are CB1 Agonists?
CB1 agonists are substances that mimic the action of endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), by binding to CB1 receptors and triggering a biological response. These agonists can be natural, like tetrahydrocannabinol (THC) from cannabis, or synthetic, such as certain pharmaceutical drugs designed to target the ECS.
Mechanism of Action
CB1 receptors are G-protein-coupled receptors (GPCRs), which means they influence intracellular signaling pathways when activated. When a CB1 agonist binds to the receptor, it triggers a cascade of biochemical reactions:
Inhibition of Adenylyl Cyclase – This reduces cyclic AMP (cAMP) levels, leading to decreased activation of protein kinase A (PKA), which ultimately affects neurotransmitter release.
Modulation of Ion Channels – CB1 activation leads to the inhibition of voltage-gated calcium channels and activation of potassium channels, reducing neuronal excitability and neurotransmitter release.
Neurotransmitter Regulation – By inhibiting the release of neurotransmitters like glutamate, dopamine, and GABA, CB1 agonists can influence mood, pain perception, and cognitive function.
Effects of CB1 Agonists
The physiological and psychological effects of CB1 agonists depend on the dosage and specific compound used. Some of the key effects include:
Euphoria and Relaxation – Common with THC, which activates CB1 receptors in the brain’s reward pathways.
Pain Relief – By modulating pain signaling in the central nervous system.
Appetite Stimulation – Often referred to as the “munchies,” this effect is commonly observed with THC.
Cognitive and Motor Impairment – Excessive CB1 activation can impair memory and coordination.
Anxiolytic or Anxiogenic Effects – Depending on the individual and dose, CB1 agonists may reduce or increase anxiety.
Current Applications of CB1 Agonists
CB1 agonists have shown promise in treating several conditions. Click here to learn more about their use.
Pain Management: Synthetic CB1 agonists such as dronabinol and nabilone are used to alleviate chronic pain in cancer and neuropathic disorders[4].
Appetite Stimulation: These compounds have been prescribed to counteract weight loss in patients undergoing chemotherapy or suffering from HIV/AIDS[5].
Neuroprotection: Research suggests that CB1 activation can protect against neurodegenerative diseases such as Alzheimer’s and Parkinson’s by reducing excitotoxicity and inflammation[6].
Mental Health: While THC can induce psychoactive effects, regulated CB1 agonists may have potential in treating anxiety and PTSD[7].
Risks and Considerations
While CB1 agonists offer potential therapeutic benefits, excessive or prolonged activation of CB1 receptors can lead to:
Cognitive Impairment
Dependency and Tolerance
Increased Risk of Psychosis in Susceptible Individuals
Cardiovascular Effects, Such as Increased Heart Rate
Figure 2 . This figure shows the interaction of CB1 agonsit with receptor to enhance pain management.
A Future of Possibilities
Despite its immense potential, cannabinoid research faces hurdles, particularly due to legal and regulatory challenges surrounding cannabis. While THC—the psychoactive component of marijuana—activates CB1 receptors, leading to its well-known effects, research is focusing on developing therapies that harness the benefits of the ECS without unwanted side effects.
Understanding cannabinoid receptors isn’t just about cannabis—it’s about unlocking new treatments for some of the most challenging neurological diseases. As research progresses, the potential for cannabinoid-based medicine continues to grow. The more we explore this system, the closer we get to innovative therapies that could transform lives.
So, the next time you hear about cannabinoids, remember—they’re not just about recreational use. They’re part of a sophisticated system that could hold the key to better brain health.
Footnotes
[1] Abrams, D. I., et al. (2003). Cannabis in painful HIV-associated sensory neuropathy. Neurology.
[2] Aso, E., & Ferrer, I. (2014). Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic. Frontiers in Pharmacology.
[3] Blessing, E. M., et al. (2015). Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics.
[4]Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience.
[5] Laprairie, R. B., et al. (2016). Biased CB1 cannabinoid receptor signaling in Huntington’s Disease. Molecular Pharmacology.
[6] Mechoulam, R., & Parker, L. A. (2013). The endocannabinoid system and the brain. Annual Review of Psychology.
[7] Mechoulam, R., & Shohami, E. (2007). Endocannabinoids and traumatic brain injury. Molecular Neurobiology.
[8] Otero-Romero, S., et al. (2016). The role of cannabinoids in multiple sclerosis treatment. Multiple Sclerosis Journal.
[9] Pertwee, R. G. (2010). Targeting the endocannabinoid system with cannabinoid receptor agonists. Philosophical Transactions of the Royal Society B.
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.
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.
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:
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.
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.
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.
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
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
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
