Disease

What Wnt wrong in Schizophrenia

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What is Schizophrenia:

Schizophrenia is a chronic brain disorder that is characterized by delusions and hallucinations. Delusions are false beliefs that an individual believes to be true. Delusions can be misinterpreting someone’s actions to be something more to the person with schizophrenia. Another symptom is hallucinations, hallucinations are where the individual experiences auditory and visual stimuli of something that does not exist. A majority of hallucinations are linked to hearing voices that are not present. Currently little is known about the cause of Schizophrenia and there are not any definite treatments.

Schizophrenia causes:

Numerous studies have looked at Schizophrenia to determine what causes and no clear-cut definite result has been determined. However, it has been observed that infection in utero has been linked to disrupting fetal brain development and contribute towards the child developing schizophrenia. A marker for schizophrenia at a young age is the delay of reaching cognitive milestones. Additionally, there has been a link between brain size and those diagnosed with Schizophrenia. Those diagnosed with schizophrenia have been observed to have less gray matter due to synaptic pruning and to have a smaller hippocampus and amygdala compared to an individual without schizophrenia.

Research has also looked at the genetics of schizophrenia and found that it is heritable. However, through exome sequencing it was discovered that a chromosomal mutation was responsible for the disease. A mutation on chromosome 14q32 reduces the production of the protein Akt. An imbalance of Akt has been linked to schizophrenia due to the protein’s role in the Wnt pathway.

Wnt pathway:

The Wnt signaling pathway is responsible for neural circuitry development and synaptic plasticity. The Wnt pathway is activated by the binding of Wnt ligands to the frizzled receptor which results in the dissociation of the destruction complex and the decreased phosphorylation of β-catenin. This allows for the accumulation of β-catenin and for the translocation to the nucleus for gene transcription. However, in the absence of the Wnt ligand binding the Axin, APC, CK1α complex is destroyed. The destruction of this complex leads to the activation of GSK-3β and the proteasomal degradation of β-catenin. The consequence of this is that GSK-3β will continue to tag β-catenin for degradation not allowing it to continue to the nucleus. Without proceeding to the nucleus for gene transcription cell differentiation, proliferation, and apoptosis are not able to be carried out.

Schizophrenia treatments

Schizophrenia is characterized by a reduction in β-catenin. Due to β-catenin being produced by the Wnt pathway dysfunction of the pathway is the leading cause of Schizophrenia. Therefore, activation of the Wnt signaling pathway is hypothesized to aid in the treatment of schizophrenia. One treatment method would be to inhibit dopamine signaling on the D2 receptor. Overabundance of dopamine has been recorded as a precursor to schizophrenia and directly activates GSK-3β, in turn degrading β-catenin. Therefore, by inhibiting dopamine Wnt signaling could be stabilized. Another potential treatment is Lithium, lithium directly inhibits GSK-3β since it competes with the binding of magnesium. Lastly, treatments that target metabotropic glutamate receptors could be a potential treatment. Targeting these receptors would increase Akt activation, decrease GSK-3β activation, ultimately resulting in β-catenin accumulation.

Conclusion

Schizophrenia is a life altering disorder that leaves individuals with numerous debilitating symptoms. However, with the help of current research a link between the Wnt signaling pathway and schizophrenia has been found. With this knowledge schizophrenia may be more effectively treated since the dysfunctional pathway is known. By knowing that reduced β-catenin levels due to the dysfunction of Wnt signaling are the culprit for schizophrenia drugs that target the activation of the Wnt pathway, inhibit D2 dopamine receptors, inhibit GSK-3β, or activate Akt are potential treatments for raising β-catenin levels and ultimately treating schizophrenia.

References

  1. Feature image: https://www.tpr.org/bioscience-medicine/2018-12-06/san-antonio-man-working-to-erase-stigma-of-schizophrenia
  2. Pathway schematic: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0471-6
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Treatment of Schizophrenia

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Treatment of Schizophrenia

Schizophrenia is a very consequential mental illness, its effects can alter how someone can think, feel, and act. Often it tends to go untreated. According to WHO only 31.3% of people with schizophrenia get treatment from specialists. You might ask yourself “if help is offered, why don’t people get the help?” Well, it isn’tthat easy.

Pathways Targeted by Anti-Psychotics.

There are four major pathways that anti-psychotics can target. The mesolimbic pathway is altered because people with schizophrenia have too much dopamine. This can cause satisfaction, emotions, and thoughts not be the same. Anti-psychotics lower dopamine transmission.  The mesocortical pathway controls cognition and reward processing. The nigrostriatal pathway controls movement can cause things like tics.  The tuberoinfundibular pathway gets effected by the high dopamine levels by causing too much prolactin. This causes the hysteria and hallucinations.

Most anti-psychotics target dopamine receptors in the brain. They block the receptors so that dopamine isn’t processed that cause the symptoms of schizophrenia. Which again you still might be asking yourself “why don’t they take the treatment?”

What Happens at These Receptors?

Antipsychotics cause D2 receptors to inhibit the enzyme Akt. Akt is responsible for the phosphorylation of GSK3β. Antipsychotics cause the GSK3β to be inhibited.

In medicated schizophrenia patients compared to ones not treated with an anti-psychotic, non- medicated had 5.8% more active D2 receptors.

The dopamine D2 receptor releases clozapine and quetiapine (both are commonly used to treat schizophrenia) more rapidly than it do any of the other antipsychotic drugs.

Perceived Effects of Anti-Psychotics

It inhibits dopamine transmission; it can cause people’s lives to become dull. Sadly, it seems to be a hit or miss acting. Yes, anti-psychotics can stop extreme symptoms, but it also inhibits dopamine transmission for typical everyday life. There are things in life that naturally produce dopamine you don’t even think of. Any sort of action or activity that gives you satisfaction gets dulled while on anti-psychotics. I am not sure about you, but simple things even like selfcare Sunday night to get ready for the upcoming week is something I look forward too. I get so much satisfaction from doing a facemask and crawling into a freshly washed and made bed. While on anti-psychotics, that wouldn’t be rewarding. It can cause people to be a lot less motivated.

Another factor that often gets mentioned is the stigmatism about taking “anti-psychotics.” Think of the word means, I personally think “undoing-the delusion.” As much as I don’t want to say it, but in society it is made to seem if you take anti-psychotics you are “crazy.” Which I can understand how that stigmatism happened due to some cases of symptoms. Yet, if we all had the same unbalance within ours brains we’d be “crazy” too. At the end of the day, we don’t and we can’t undo it for others that do. So truly tagging such negative ideals to something so impacting such a schizophrenia is unfair. Those that deal with it are already just trying to deal with impacts.

The Future of Treatment

As time goes on so does research, more suitable treatment plans are being investigated. A middle ground, not an all or nothing strategy is the goal. Recently an oral compound SEP-363856, has been studied as a medication for schizophrenia. A 2020 study posted to the New England Medical Journal has studied SEP-363856. It isn’t a D2 inhibitor, but an agonist at TAAR1. TAAR1 is a G-coupled protein receptor that has been shown to alter dopamine, serotonin, and glutamate activity. It is currently in phase 3 of clinical testing. Most studies were short, (around 4 months long) yet have shown positive results. The only one thing negative thing I can find so far on this drug is that it may be suitable for mild Schizophrenia cases. Another note on treatment plans I found is that majority of treatment is being done to treat Schizophrenia. There isn’t much being done or real definitive answers to help the physical brain matter of people with Schizophrenia. That not too much can be done for preventative care.

A Peak into Schizophrenia

I found this little youtube video that has a young boy with schizophrenia and his treatment team. I think it is worth the watch. You can read as much as you want to try to understand what symptoms may be like, this video helps me see what it is somewhat like going off of this real life story. It also mentions another treatment plan that is in clinical trial, this one focuses on the auditory system. Which personally blows my mind that so far it seems to be effective. It doesn’t effect dopamine pathways which cuts out the bad effects of anti-psychotics. Instead it helps with auditory hallucinations. It targets the processings within the brain.

 

Sources

https://www.who.int/news-room/fact-sheets/detail/schizophrenia
https://pubmed.ncbi.nlm.nih.gov/32294346/
https://psychopharmacologyinstitute.com/publication/the-four-dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096
https://www.nature.com/articles/s41398-021-01331-9#:~:text=SEP%2D363856%20is%20a%20trace,for%20the%20treatment%20of%20schizophrenia

 

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Schizophrenia in the developing mind

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Schizophrenia is hypothesized to be a brain developmental disorder that can be diagnosed or evident in late adolescence or early adulthood. This mental illness disorder can be characterized by hallucinations, delusions, social withdrawal, and cognitive disabilities. The main concern with this disorder is that the onset can be in adolescence childhood, which is a critical period for the brain’s neural development and growth. Therefore, the main question is how do we focus more on prevention along with treatment for Schizophrenia?

In a brain with Schizophrenia it is evident that there is cortical thinning in the superior temporal gyrus and patients with Schizophrenia have a smaller hippocampus, amygdala, thalamus. Suggesting a possible correlation to Alzheimer’s disease as the hippocampus is the first portion of the brain to be affected. Therefore, with a smaller brain volume there is greater lateral and ventricle volumes and as a result greater cerebrospinal fluid. In terms of genes, the protein C4 from a C4 gene on chromosome 6 puts an individual at greater risk for Schizophrenia.

As related to the article, An emerging role for Wnt and GSK3 signaling pathways in schizophrenia, the pathway related to Schizophrenia is the Wnt signaling pathway. This pathway is based in the role it plays in the neural development to adult neural circuit function as it relates to Schizophrenia. During developmental stages patients with schizophrenia may show delays in certain milestones such as problems with neuromotor development, poor performance on cognitive tests, problems with speech, and difficulties in social adjustment. As it relates to development, studies have suggested that there is a correlation between utero and early environmental factors like infection that could play a role during pregnancy in later development of Schizophrenia. Therefore, disrupting fetal brain development from unfortunate events during pregnancy and increasing the risk of child to develop Schizophrenia.

 

https://doi.org/10.1111/cge.12111

As briefly discussed in small break out groups, prenatal vitamins were suggested to possibly have part to increase the likelihood of developing schizophrenia in the child later on. However, from a nutrition standpoint prenatal vitamins contain important nutrients such as folic acid or folate that help to drastically decrease the risk of the fetus having spina bifida. On the argument that prenatal vitamins could increase the risk, I question the role folate plays with schizophrenia. As a result in vitro and in vivo studies suggest that folate deficiency increases risk of Schizophrenia in the developing fetus. Considering that with folate deficiency there is also higher levels of homocysteine that can build up in the blood. Homocysteine creates greater risk for not only cardiovascular disease but also negatively impacting brain development from neuronal dysfunction in a developing fetus. Higher homocysteine levels have also been seen in patients with Alzheimer’s disease or other forms of dementia.

Along with this, a prenatal supplement in the nutrition world is understood as a supplement; a supplement should go along with proper nutrition from food otherwise the effects and benefits could be impacted. Nutrition plays a key role in fetal development early on and as a more recently discovered mental illness there is still a lot to learn about Schizophrenia. More research is needed on the topic of when Schizophrenia develops and whether or not there are ways to prevent it or better treat this disorder.

 

Citations:

Schizophrenia’s strongest known genetic risk deconstructed. NIH, 2016. https://www.nih.gov/news-events/news-releases/schizophrenias-strongest-known-genetic-risk-deconstructed

An emerging role for Wnt and GSK3 signaling pathways in Schizophrenia. Singh, KK. Developmental Biology: Frontiers for clinical genetics, 2013. Wiley Online Library. https://doi.org/10.1111/cge.12111

Childhood developmental abnormalities in Schizophrenia: evidence from high-risk studies. Suvisaari, J., tuulio-Henriksson, A., Lonnqvist, J. Schizophrenia Research, 2003. Science Direct. https://www.sciencedirect.com/science/article/pii/S0920996402002347?via%3Dihub#BIB12

The Origins of Schizophrenia, edited by Alan Brown, and Paul Patterson, Columbia University Press, 2011. ProQuest Ebook Central, https://ebookcentral.proquest.com/lib/cord-ebooks/detail.action?docID=909358.

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What causes Schizophrenia and how can we stop it before it becomes a problem?

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Bipolar disorder, major depression, and schizophrenia are psychiatric conditions that make daily life difficult for many in society. Whether it’s the person who suffers from the disease, their family and friends, or even their caretaker, schizophrenia can be especially difficult to handle. Characterised broadly as a condition where someone’s reality is viewed abnormally, those with schizophrenia can experience disorderly thinking that can lead all the way to having hallucinations and delusions. This can impair their daily life often leading to the need for full time care and oversight. Current schizophrenia treatments include the use of antipsychotic medications which often have multiple side effects to the patient, ultimately leading to a low patient compliance. Beyond the lack of current treatment, the factors that contribute to the diagnosis are still under scrutiny. At a basic level, schizophrenia can see its rise from interruption of proper neural development in adolescence. A review by Michaud and Pourquie dove into the molecular pathways that have shown potential contributing factors to this developmental dysfunction. 

Two Important Molecules

Michaud and Pourquie devoted their attention to a molecular pathway that involves two molecules, Wnt and GSK3β. Wnt is a molecule that binds outside of the cell and is responsible for maintaining the activation of GSK3β inside of the cell. GSKβ, when it is activated by Wnt receptors, will inhibit the action of another molecule called β-Catenin. β-Catenin is responsible for the transcription of genes in the cell nucleus that are pivotal for proper neurological development. Thus, schizophrenia at its simplest form may be linked to the inhibition of β-Catenin by Wnt and GSK3β signalling. 

Above is Figure 2 from the review placed next to a simplified depiction of the two factors that affect β-Catenin and subsequent development of schizophrenia.

Multiple different factors are being studied that affect Wnt-GSK3β signalling. One of the biggest molecules that contributes to this is dopamine. When there is a high amount of dopamine signalling, a cell will allow GSK3β to remain in its active state. When this occurs, β-Catenin will remain inhibited. This will lead to dysfunction of cell development. 

Genetics

Genetics are also being considered as a factor that contributes to the development of schizophrenia. Research has assessed specific genes that may contribute to the disease along with specific changes to the individual “codes” that make up a DNA message; these are called single nucleotide variants. There are also copy number variants, which are composed of multiple genes. These can contribute to the development of schizophrenia by affecting the proper development of neurons whether it be through its affect to signalling mechanisms or other factors. Animal models are currently being used to assess these genetic factors but more research is needed.

Looking Into The Future

Schizophrenia can appear in adolescence and can occur from both interruptions to normal cellular signalling along with other genetic factors. Seeing that it has a strong relation to neural development, monitoring of the conditions that lead to schizophrenia development may serve valuable. Developing monitoring systems for chemical signalling like Wnt and GSKbeta may help assess abnormality in neural development before it becomes a problem. This can also apply to assessing for genetic variation in an individual through genome sequencing. These two interventions, however, both come with costs and ethical considerations. However, as we build understanding, we may soon have ways of assessing the development of schizophrenia before it becomes too late to fix it. 

Jacques L. Michaud and Oliver Pourquie, “An emerging role for Wnt and GSK3 signaling pathways in schizophrenia.” Clinical Genetics 83, 511-517, (2013)

 

Disease

Schizophrenia: Cell Signaling to Hallucinations

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Introduction to schizophrenia

Schizophrenia is a psychiatric disorder affecting millions worldwide. Most commonly, schizophrenia is associated with positive symptoms such as hallucinations and delusions, and negative symptoms such as impaired day-to-day task functioning and decreased social interest. Although the disorder is common and easily identifiable and diagnosed, schizophrenia is not highly understood biologically, leaving effective treatments and preventative actions having yet to be discovered. 

Schizophrenic patients are typically diagnosed in late teen or early adult years and symptoms can begin to arise years prior to diagnosis. But what causes or triggers the onset of this disorder in children or young adults? Studies have revealed that schizophrenia begins early in life with disrupted brain development (infection in utero, cognitive delays in early childhood, etc.). A key player in brain and cognitive development is the Wnt signaling pathway, and disruption of this signaling cascade is when schizophrenic symptoms develop. 

Wnt signaling and schizophrenia

Wnt binds to frizzled receptors and recruits proteins to the membrane which causes dissociation of a beta-catenin destruction complex, and beta-catenin then transports to the nucleus for transcription. Without Wnt binding, this destruction complex containing the protein GSK3-beta, phosphorylates beta-catenin, targeting it for destruction. Beta-catenin gene transcription in the nucleus is crucial for cell proliferation, differentiation, and apoptosis (programmed cell death). Schizophrenia patients have been found to have decreased beta-catenin levels, implying Wnt signaling dysfunction in these patients.

Wnt signaling is essential for synaptic plasticity – change that occurs in response to neuronal activity at synapses that strengthen or weaken communication between neurons over time. With the dysfunction of Wnt signaling in schizophrenic patients, synaptic plasticity is decreased and with that decrease comes the loss of neuronal excitability. A doctor studying the correlation between Wnt signaling, synaptic plasticity, and schizophrenia symptoms inferred that the altered cognitive function, or the onset of negative symptoms, of those with schizophrenia begins with this loss of neuronal excitability. Then, the positive symptoms arise by the brain and body compensating for this loss of excitability – essentially, inhibiting the inhibition – which causes randomized firing that causes the hallucinations most often associated with schizophrenia.

 

References

Guildford, A. (2021, September 9). Schizophrenia: synaptic dysfunction plays a key role. Medical News Today. Retrieved February 19, 2023, from https://www.medicalnewstoday.com/articles/schizophrenia-synaptic-dysfunction-plays-key-role

Jia, L.; Pina-Crespo, J.; Li, Y. (2019). Restoring Wnt/B-catenin signaling is a promising therapeutic strategy for Alzheimer’s Disease. Molecular brain, 104(2019). https://doi.org/10.1186/s13041-019-0525-5

Singh, K. 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

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Wnt Signaling’s  Role in Schizophrenia

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What is Schizophrenia

Schizophrenia is a psychiatric disorder that is hallmarked by an individual’s abnormal interpretation of reality that interferes with their everyday lives. There are two categories of symptoms which are positive and negative symptoms. People with schizophrenia can display both types of symptoms at different times. The positive symptoms include delusions, hallucinations, disorganized thinking, and disorganized behavior. The negative symptoms include things such as lethargy, lack of emotion, and general loss of interest in social activities.

Delusions: beliefs that are false and have no foundation in reality. Like if a person believes that they are the president of the United States.

Hallucinations: having a sensory experience without the presence of any actual stimulus. Like when you think you hear your name, but no one has said anything in the last five minutes.

Disorganized thinking patterns: this is marked by impaired speech patterns. Usually, people displaying this symptom may answer questions with words that aren’t relevant to the question, or they will string a bunch of random words together to make an incoherent sentence.

Disorganized behavior: this is marked by things such as strange posture and actions that have no clear goals, such as excessive movement.

Wnt Signaling Overview

Wnt signaling is a type of cell signaling that cells use to initiate gene transcription so they can make proteins. These proteins then are used for the normal functioning of the cell. The goal of Wnt signaling is to activate a chemical called B-catenin that is used to initiate gene transcription. Wnt is a signal that binds to a certain receptor in the cell membrane (called frizzled). Once frizzled is activated it recruits this complex of proteins called the destruction complex. Normally, this destruction complex is deactivating B-catenin, but when it is called away by frizzled than B-catenin is free to enter the nucleus and do its thing.

Michaud, J. L & Pourguie, O. (2013) an emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clinical Genetics 83, 511-517. Doi: 10.1111/cge.12111.

Wnt Signaling in Schizophrenia

Schizophrenia is marked by a decrease of activity from a neurotransmitter (a chemical that neurons used to communicate with each other) called dopamine (DA). This is bad because DA indirectly helps to regulate the Wnt signaling pathway. As I mentioned before the destruction complex used to deactivate B-catenin contains a certain enzyme called GSK3B. Usually DA is able to indirectly activate this enzyme which helps keep the B-catenin levels under control. But when DA isn’t able to help out then B-catenin is overactive, and this can cause problems in the cell.

This is why many antipsychotic drugs that are used as a treatment for schizophrenia target DA levels. Specifically, they try to increase DA levels. When DA is more active it is better able to keep the GSK3B enzyme active and B-catenin inactive. This results in better control over the gene transcription in the nucleus so the cell can better control what proteins are being produced and run better.

Michaud, J. L & Pourguie, O. (2013) an emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clinical Genetics 83, 511-517. Doi: 10.1111/cge.12111.

How to Help People with Schizophrenia

Unfortunately, there is not much that the everyday person can do if they have a loved one with schizophrenia. The most important thing is to offer your love and support for them when they are struggling. Try to encourage them to seek professional help from a psychiatrist. Of course, if there is an emergency where their health and safety is at risk then 911 should be contacted.

References 

Michaud, J. L & Pourguie, O. (2013) an emerging role for Wnt and GSK3 signaling               pathways in schizophrenia. Clinical Genetics 83, 511-517. Doi: 10.1111/cge.12111.

https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443

Disease/Health

The Maze of the Mind: Navigating the Complexities of Schizophrenia

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Artstract by Timea Vrabcová (using DALL.E)

Schizophrenia is a complex mental disorder that is characterized by a range of symptoms including delusions, hallucinations, disordered thinking, and abnormal behaviors. It is a chronic illness that typically appears in early adulthood and can have a significant impact on individual’s perception of reality [1]. While the exact cause of schizophrenia is not fully understood, recent studies have suggested a link between schizophrenia and the Wnt signaling pathway.

 

Symptoms

One of the hallmark symptoms of schizophrenia is the presence of hallucinations and delusions [2].

  • Hallucinations = perceptual experiences that occur in the absence of external stimuli
  • Delusions = fixed, false beliefs that are not based on reality

These symptoms can be extremely distressing and can interfere with a person’s ability to function in daily life. The exact neural mechanisms underlying these symptoms are not yet fully understood, but it is thought that they may result from abnormalities in the brain’s sensory processing systems, as well as abnormalities in the connectivity between different brain regions.


Causes

One of the primary causes of schizophrenia is the dysfunction of dopamine signaling in the brain. This leads to an overstimulation of dopamine receptors, which causes an imbalance in the communication between the neurons.

Another significant factor in schizophrenia is the reduction in the size of certain brain structures, including the hippocampus and prefrontal cortex. The hippocampus is responsible for memory formation and retrieval, while the prefrontal cortex controls decision-making, planning, and attention.

One of the prevailing theories of schizophrenia is that it results from a combination of genetic and environmental factors. Environmental factors such as prenatal exposure to viruses, early childhood trauma, and drug use may also increase the risk of developing schizophrenia.

 

How is Schizophrenia Studied?

The brain abnormalities associated with schizophrenia have been extensively studied using advanced imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). These studies have shown that people with schizophrenia have structural and functional abnormalities in prefrontal cortex and hippocampus.

  • Wnt Pathway 
    The Wnt signaling pathway is a complex network of proteins that play a critical role in embryonic development, tissue homeostasis, and cell differentiation [3]. The pathway is activated by the binding of Wnt ligands to cell surface receptors, leading to the activation of downstream signaling pathways. Alterations in Wnt signaling may contribute to the dysfunction of neurotransmitter systems involved in schizophrenia, such as dopamine and glutamate and disrupt emotional and cognitive processing [4].
  • Animal Models [5]
    Studies investigating the development of schizophrenia use animal models, especially mice and rats due to their complex social behavior and genetic similarity to humans [6]. Blocking the Wnt pathway during brain development led to the development of schizophrenia-like symptoms in mice. Specifically, the mice exhibited deficits in working memory, social behavior, and sensory gating, which are all symptoms commonly seen in schizophrenia. These findings provide further evidence of a link between Wnt signaling and schizophrenia.

 

What is the Treatment for Schizophrenia?

The most commonly used treatments are antipsychotic medications, which work by blocking dopamine receptors in the brain. While these medications can be effective in reducing the positive symptoms of schizophrenia such as hallucinations and delusions, they may not be effective for all individuals and can cause significant side effects, such as weight gain, sedation, and movement disorders. Other treatments that may be helpful for people with schizophrenia include cognitive behavioral therapy (CBT) and family therapy, which can help individuals and their families manage the condition and improve their quality of life.

 

Conclusion

Schizophrenia is a complex mental disorder that affects millions of people worldwide. Further research is needed to fully understand the mechanisms by which Wnt signaling contributes to schizophrenia and to develop effective treatments for this debilitating condition. By increasing awareness and understanding of schizophrenia, we can help to reduce the stigma associated with mental illness and improve outcomes for those affected by this challenging disorder.

 

Sources

  1. https://www.nimh.nih.gov/health/topics/schizophrenia
  2. https://www.verywellhealth.com/schizophrenia-sign-symptoms-5095511
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967064/#:~:text=Axin%2C%20a%20key%20component%20of,6%20and%20facilitates%20the%20recruitment ▲
  4. doi: 10.1111/cge.12111
  5. https://elifesciences.org/articles/54020
  6. https://www.cyagen.com/us/en/community/technical-bulletin/mice-vs-rats.html
Disease/Health/Uncategorized

Reducing the Risk of Schizophrenia Through Prenatal Nutrition

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Schizophrenia is a mental illness characterized by negative and positive symptoms. Positive symptoms include delusions and hallucinations. Delusions are beliefs that are untrue. Hallucinations are things that people see or hear that are not really there. Negative symptoms include loss of interest in daily activities, loss of motivation, and social withdrawal. Those with Schizophrenia are usually diagnosed between the ages of 16 and 30. Unfortunately, little is understood about the causes of schizophrenia, but it is believed to emerge from a combination of genetic and environmental factors.1

Genetic Factors

The gene primarily associated with schizophrenia is DISC1 (disrupted in schizophrenia 1 protein). DISC1 was found in a Scottish family that had cases of schizophrenia, bipolar disorder, and major depressive disorder. DISC1 plays a role in developing new neurons in the hippocampus, which is involved in memory and learning, during embryonic development and in adulthood. Abnormalities in this gene is linked to schizophrenia.2

Additionally, DISC1 also plays a role in Wnt signaling. In this figure we see that GKS3β acts on β-catenin, a protein. When Wnt is not active, GSK3β causes the phosphorylation of β-catenin which leads to degradation. If GSK3β is inhibited through Wnt binding, β-catenin is not phosphorylated and is able to enter the nucleus to stimulate TCF/LEF gene transcription.

DISC1 directly inhibits GSK3β which allows β-catenin to stimulate TCF/LEF gene transcription.3 (paper) But, if DISC1 is abnormal, TCF/LEF is not stimulated and cells in the hippocampus cannot form during development.4 

Environmental Factors

One possible hypothesis is that schizophrenia stems from issues in brain development. Some studies show that disruptions during pregnancy can increase the risk of schizophrenia in offspring. In general, those with schizophrenia have been shown to have lower cognitive ability than the general population. Further, people with schizophrenia had experienced developmental cognitive delays in their childhood.3 

One environmental factor is fetal exposure to infection. One study has shown that pregnant women that become infected with influenza during the first half of the pregnancy produced an increased risk of schizophrenia in the child. Maternal exposure to herpes simplex virus 2 and rubella also showed an increased risk of schizophrenia in the child.

But prenatal malnutrition has also shown to create a risk for schizophrenia. Specifically, a maternal lack of vitamin D and homocysteine, a micronutrient, can increase the occurrence of schizophrenia. Additionally, in times of famine, schizophrenia had increased in offspring.5

What Can We Do?

One option to decrease the risk for schizophrenia would be addressing environmental issues, specifically, nutrition. In a study looking at the effects of nutrition on fetal development’s association with offspring’s mental health, it was found that proper nutrition during pregnancy promoted healthy fetal development and decreased the incidence of mental illness. Supplementing vitamins A and D was found to decrease the risk for schizophrenia while the use of omega-3 fatty acid before 20 weeks gestation increased the risk for schizophrenia.6 Although there are many environmental factors that affect fetal development, like malnutrition and exposure to infection, focusing on controlling nutrients may be a way to prevent schizophrenia.

  1. https://www.nimh.nih.gov/health/topics/schizophrenia
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722990/
  3. Singh, K. 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
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763761/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691516/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984656/#:~:text=Omega%2D3%2Dfatty%20acid%20supplementation,childhood%20wheezing%20and%20premature%20birth.
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BCL9 and Beta-Catenin’s Functioning in Schizophrenia

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Artstract by Dhruvika Patel

What is Schizophrenia?

Before looking at pathway dysfunction, it’s important to understand what exactly schizophrenia is and its implications. Schizophrenia is a mental condition that can be triggered from not one specific pinpoint of dysregulation, but rather a variety of different genetical, psychological, and environmental factors. This makes preventative measures difficult to take. While it affects less than one percent of the U.S. population, the effects are far from easy to live with. But what exactly does having schizophrenia imply? It normally involves delusions, hallucinations, disorganized speech, grossly disorganized behavior, and withdrawal from social activities. Two or more of these should be seen for a significant amount of time and cannot be due to substance abuse to diagnose an individual with schizophrenia.

Schizophrenia is typically diagnosed in people in their late teens to early thirties, so it is not a condition that necessarily comes with old age. Males are more likely to be

The blue bars represent men vs the red bars representing women for when they are diagnosed with Schizophrenia. More men are diagnosed earlier than women. (1)

diagnosed earlier in their lives than females are; however, this is a condition that is often difficult to recognize in the early phases. To recognize it earlier, symptoms to look for with thinking may be problems with reasoning, bizarre ideas or speech, or confusing dreams or television for reality. Early behavioral problems could include withdrawal from family and friends, trouble sleeping, lack of motivation, not meeting daily expectations, or violent or aggressive behaviors. Emotionally, they would be irritable or depressed, have a lack of emotion, have strange anxieties and fears, or just be very suspicious of others. The range of earlier symptoms could be difficult to tie directly to schizophrenia and not anything else, but as they age, more typical signs and symptoms (ie. delusions, etc.) will appear.

Wnt Signaling and Schizophrenia

Patients with schizophrenia have a lower cognitive ability which may be a result of wnt signaling pathway development or rather lack of. The beta-catenin functioning properly in the wnt-signaling pathway is vital in synaptic plasticity of the neurons in human brains. Normally, GSK will be inhibited in the wnt-signaling pathway, which will allow beta-catenin to get to the nucleus. If GSK is not inhibited, it will tag the beta-catenin to go to the proteosome instead to be destroyed. Beta-catenin’s interactions in the nucleus is important for cell proliferation, differentiation, and apoptosis. Beta-catenin is important for the transduction of the signal to the nucleus and once it reaches the nucleus, it can transcribe the wnt-related genes that control cell fate in cells and tissues.

BCL9 and Beta-Catenin’s success

BCL9, B-cell lymphoma 9, is often not emphasized in the wnt pathway, but it does have an important role in Beta-catenin’s proper functioning. What is BCL9 and where does it come from? B-cell lymphoma is a large protein encoded by the BCL9 gene expressed in all tissues of the body. In the wnt-pathway it works with another protein, PYGO, to tether Beta-catenin to TCF/LEF. This tethering allows for efficient T-cell factor mediated transcription in the wnt signaling pathway; without it, the beta-catenin may not properly bind to the transcription factors to transcribe the necessary genes. Think of BCL9 acting like cupid to bring the transcription factors and beta-catenin together.

(2)

Conclusion

Schizophrenia is not necessarily an easy condition to diagnose until the symptoms become more obvious. It makes one wonder possibilities for what may be causing this. One pathway that alterations can cause problems with is the wnt pathway. The wnt signaling pathway is composed of such a variety of components that affect its proper functioning. The final goal is for beta-catenin to transcribe the appropriate genes, and dysfunction here can lead to a multitude of mental disorders including Schizophrenia. One of the many important components of the success of this pathway includes BCL9, with its function vital in tethering the beta-catenin to the transcription factors.

Citations:

  1. https://www.nature.com/articles/s41537-020-0102-z
  2. https://www.nature.com/articles/s41375-019-0404-1

 

Community/Disease/Health/Uncategorized

Gaining Empathy for the Mentally Ill: Schizophrenia Edition

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Schizophrenia is a debilitating disease that effects 24 million people worldwide, 2.8 million of those people being in the United States. Schizophrenia is a disease that affects how a person, thinks, feels, and behaves. There are people, just like you and me, that are struggling with hallucinations, delusions, disorientated thinking, and impaired daily function.

When diagnosing schizophrenia, there are two sets of symptoms that are quite distinguishable. A psychologist will be looking for positive and negative symptoms. Positive symptoms include hallucinations, delusions, and disorganized speech. Negative symptoms include flattened affect, reduced speech, and lack of initiative.

It has been proposed that schizophrenia might develop sooner than we have previously seen. Most people get diagnosed in adolescence, but it is hypothesized that abnormalities could begin in utero along with early environmental influences such as infection.

Changes in the Brain: Physical and Molecular

There are many changes that can be seen in the brain when looking at people diagnosed with schizophrenia. Smaller total volumes of brain tissue and less gray matter. Schizophrenia affects many adolescents and young adults, so the image to the right shows the rate of gray matter loss in schizophrenic adolescents. It can be seen that there is a faster rate of loss within the parietal (top) and temporal (side) parts of the brain.

Those are some physical changes in the brain that can be seen by imaging. There are molecular changes that are happening in the brain that can’t totally be seen. Schizophrenia can be linked to the Wnt pathway, which with more research, can help lead to better treatments.

Overactive dopamine is binding to its receptors (D2) which inhibits the Akt enzyme. The inhibition of this enzyme will in turn decrease the inhibitory phosphorylation of GSK3-beta. If GSK3-beta is not inhibited, it will remain a destruction complex in the Wnt pathway. With this complex still in place, beta-catenin will continue to break down and gene transcription does not happen. Without gene transcription, genes important for neural development will not be expressed. When these genes are not expressed, abnormal functioning and development occurs which can ultimately lead to schizophrenia.

Schizophrenia is a complex disease that is very difficult to study and research. It is hard to model schizophrenia in a lab which is why the treatment options and research is so slow. Finding out the that Wnt pathway is involved in schizophrenia is a big advancement in the etiology and treatment of this disease. With new genetic findings and animal and human stem cell models, there will be the ability to gain a deeper understanding of all neuropsychotic disorders not just schizophrenia.

How to Gain Empathy for the Mentally Ill

Mental illness can change the course of someone’s entire life. Even with treatment, their life will be filled with psychiatrist appoints, therapy sessions, pharmacy visits, and people treating them differently. The negative stigma around mental illnesses has gotten better over the years, but there is always room for change and improvement.

People with mental illnesses cannot help it. It is not their fault, and it never will be. They can barely get the help that they need so we do not need to add to the stress. I think that education and advocation is something every person should care more about when it comes to the mentally ill. Taking the time to research a mental illness or asking respectful questions or standing up for people with mental illness when they are not able to stand up for themselves is essential.

There are many TV shows, movies, and books that depict the life of those with mental illnesses. While these can bring awareness to living with mental illnesses it is important to remember that these are more than likely dramatized and do not show accurate depictions of what it is really like to live with these types of illnesses.

One of the best books that I have read that accurately shows schizophrenia and what it is like is the book called Challenger Deep by Neal Shusterman. This book follows a young boy who has schizophrenia and his daily struggles. We get a glimpse into the mind of someone with schizophrenia and this sort of thing hasn’t been done too often.

 

 

References:

Jodi Clarke, M. A. (2022, May 20). Signs and symptoms of schizophrenia. Verywell Mind. Retrieved February 19, 2023, from https://www.verywellmind.com/what-are-the-symptoms-of-schizophrenia-2953120

NEALSHUSTERMAN. (2020). Challenger deep. Amazon. Retrieved February 19, 2023, from https://www.amazon.com/Challenger-Deep-Neal-Shusterman/dp/0061134147/ref=sr_1_1?crid=1H3WVMZLS747J&keywords=challenger%2Bdeep&qid=1676832807&sprefix=challenger%2Bdeep%2Caps%2C185&sr=8-1

Singh, K. 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

Wnt signaling*. WormBook Header Image. (n.d.). Retrieved February 19, 2023, from http://www.wormbook.org/chapters/www_wntsignaling/wntsignaling.html

 

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