Cobbers on the Brain

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.

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)

Insulin

Insulin is a peptide hormone with numerous functions in the body, the most common of which is to control glucose levels. Insulin acts differently in the pancreas, liver, bones, and so on than it does in the brain. Insulin regulates neuron growth, survival, differentiation, and communication in the brain. So, what happens when insulin is not properly regulated?

Insulin resistance

This is a condition in which the body and brain are unable to use glucose as an energy source effectively. The ability to be insulin sensitive is lost, and as a result, glucose absorption by brain cells is compromised. Insulin regulates brain metabolism and overworked insulin receptors cause brain cells to die. Chronic oversupply of glucose to brain cells causes the cells to overwork in order to metabolize the excess fuel, eventually giving up and committing suicide via a process known as apoptosis.  

This has an effect on neuro communication in the brain because glucose is what the cells require to function properly. At this point, the brain is essentially starving. There is an abundance of glucose but no way to use it. 

 High carb content diets, like the typical American diet promote chronic and prolonged blood sugar spikes. This prolonged glucose overdose starves the brain and later  manifests itself as cognitive impairment. Cognitive ability is directly proportional to energy supply to the brain.

Diabetes

It is critical to distinguish between type I and type ii diabetes. We lack the ability to produce insulin in type I diabetes, so glucose levels in our bodies are high. In type II diabetes, however, insulin is present, but it is excessive, and our cells become resistant to it, raising glucose levels to dangerously high levels. When we think of diabetes, we usually think of the heart, kidneys, and pancreas as the most affected organs. But what about the brain? 

Diabetes accelerates brain aging, which, as we know, causes neurodegenerative diseases such as Alzheimer’s. Blood flow to the brain is reduced in diabetic patients, causing neuron damage. These neurodegenerative changes occur at a much earlier stage. Diabetes also impairs byproduct metabolism in patients, resulting in the buildup of undesirable substances such as amyloid plaques and neurofibrillary tangles found in Alzheimer’s disease.

In diabetes, people have smaller brain volume of the frontal and temporal lobes due to brain atrophy triggered by excessive cell apoptosis.

Inflammation and Alzheimer’s Disease

When most people hear the words Alzheimer’s disease, they envision plaques and tangles. We know that amyloid plaques and neurofibrillary tangles are major indicators of neurodegenerative disease, most notably Alzheimer’s disease.

Plaques cause one of three problems in the brain:

• Disruption of neuron communication by acting a physical barriers in synapses
• Trigger inflammation through the intervention of the immune system
• Increased risk of hemorrhage in blood vessels through amyloid angiopathy

Tangles form when plaques accumulate outside of neurons. Tangles cause significant disruption in the cell’s transport system, the microtubules.

Tangles, combined with plaque buildup, eventually cause the cells to die via apoptosis. This explains why reduced brain atrophy, a condition caused by too much cell death in the brain, is a major symptom of Alzheimer’s disease.

If this blog is to be of any use to you, I want you to be able to link insulin to the formation of plaques and tangles, and, in the larger picture, Alzheimer’s disease.