Imagine if a skyscraper were constructed in such a way where they needed constant maintenance, and if they did not get it would be there natural state to collapse and be destroyed. It seems like a real backwards way to construct a building, or to maintain anything man-made or natural for that matter. So it is surprising to find out that a major chemical signaling pathway, the Wnt and GSK pathway, operates in manner that aligns with this metaphor. The natural state of this critical signaling pathway is that of destruction. The pathway must be activated by a Wnt ligand that triggers cellular events that stop a complex that is involved with destruction. If that seems a bit confusing, I was with you but bear with me. The pathway must be activated, to stop intracellular destruction, which maintains normal cell development.

So why does this matter?

The Wnt signaling pathway is integral in the development of the brain. For example, Schizophrenia is a well-known condition typically associated with disruption of this pathway. Schizophrenia and this pathway, in a nutshell, involves the destruction complex in the cell running wild and not being hindered by Wnt signaling as it should be. This makes sense because there are notable brain changes in schizophrenia involving the anatomy, and key developmental differences. These anatomical changes have some significant consequences for individuals afflicted with such a disease.

Symptoms of Schizophrenia

Most people are familiar with the positive symptoms common of schizophrenia. These would include hearing voices, and grand delusions of government conspiracies for example. These symptoms are only a small part of the wide varieties of symptoms schizophrenia is associated with. For example there are negative symptoms such as flat affect, and low motivation. These symptoms can also be accompanied with cognitive issues which can also have a substantial impact on quality of life.

Cognition and Schizophrenia

Along with positive and negative symptoms, there is a myriad of cognitive deficits typical of schizophrenia some of which are:

• Attention: a common cognitive deficit involved with schizophrenia involves attentional issues. While a neurotypical individual can multitask and focus on several objects, those with schizophrenia tend to hyper-focus on one object at a time.
• Working Memory: Attention and working memory work hand in hand. Working memory is your ability to take in information and briefly maintain and use it in an ongoing task. Generally working memory capacity is 3 to 4 simple items but it is considered less in schizophrenia. If you can only focus on one thing at a time you can only bring that one thing into your memory.
• Executive Functioning: Executive Functioning is a broad and complex topic, but it generally includes things such as planning and goal-oriented behavior. These are all considered impaired in schizophrenia as it is more difficult to bring in new information and adjust to changes.

Conclusion

It is a little wild to think that a simple, and strange signaling pathway going wrong can have such broad consequences for an organism. A signaling pathway gone awry and causing cell death in its resting state is responsible for positive, negative, and cognitive symptoms alike. How such a small molecule, such as the GSK kinase that is responsible for the destruction, can have such broad implication for an overall organism.

“Too much of anything is a bad thing”, right? The idea of balance is integral to our understanding of the world across different belief systems and at various levels. Yin and Yang are perhaps the most notable examples of opposite forces evening out a greater whole, but the concept guides our beliefs and actions in many ways, from how we prioritize commitments in our lives to what kinds of foods we consume. While a disrupted balance in how we live our life can certainly make us feel anxious, It turns out that internal balance plays a key role in anxiety as well, with two neurotransmitters called Glutamate and GABA keeping each other in check- or at least supposed to be. 

Glutamate and GABA – How do they Relate?

In terms of anxiety, Glutamate and GABA could be considered the ‘yin’ and ‘yang’ of the central nervous system. Both are highly important for sending messages between neurons; in fact, they are responsible for over 90% of neurotransmission in the brain! They have directly opposite effects, however, with glutamate sending excitatory signals that make neurons more likely to ‘pass on a message’ and GABA sending inhibitory signals that make this communication less likely. Physiological homeostasis of the nervous system is needed for proper functioning, and it requires regulation of opposing forces such as these. So, when there is an abundance of Glutamate and low levels of GABA, stress and anxiety responses are more likely to occur.  

In many areas of the brain, glutamate and GABA are intertwined within neural circuits and pathways, and this close interaction allows them to balance each other through tight regulation. For example, axons of a specific type of cell called granule cells synapse with interneurons that release GABA in the the dentate gyrus, an area of the brain’s hippocampus. The granule cells release glutamate when excited, but because the neurons they synapse on release inhibitory GABA, the glutamatergic neurons (neurons that release glutamate) that these neurons project to will in turn be inhibited. In short: excitation stimulates inhibition, and this leads to inhibition of excitation. Pathways like these provide a mechanism for regulation of anxiety, because higher levels of GABA will result in lower levels of glutamate as a way to create balance – in fact, anti-anxiety medications such as benzodiazepines work in a similar fashion to this, by enhancing inhibitory effects of GABA on glutamatergic neurons. 

Another area involved in balancing these two neurotransmitters is the amygdala, whose general function is processing fearful and unpleasant stimuli. Specifically, the Basolateral nucleus (BLA), Central Amygdala (CeA) and Bed Nucleus of Stria Terminalis (BNST), are all locations involved within the amygdala. Glutamatergic neurons in the BLA are regulated by GABAergic interneurons that lie within this area as well. The CeA has only GABAergic neurons and receives input from the BLA. All of these connections and communications serve to modulate balance of GABA in the amygdala, with GABAergic neurotransmission helping to inhibit the amygdala’s interaction with stress and anxiety. On the flip side, however, stress may cause interneuronal networks to reduce, which disrupts the excitatory and inhibitory balance and can therefore lead to neuropsychiatric disorders. Animal studies back this up: in one experiment, for example, subjecting rats to social isolation reduced the expression of GABAergic neurons in the BLA.

Balance on a Societal Scale  

While these physiological mechanisms certainly offer insight for how anxiety responses can be regulated or dysregulated in the brain, they do not explain the rapidly rising rates of mental illness in the U.S. On a societal level, the argument has been made that people with mental disorders such as anxiety and depression are “canaries” of our cultural coal mine. Just like canaries were said to warn miners of an incoming explosion by singing, people suffering from mental illness are early warning signs of imbalance in society. The canaries did not survive the explosions, and people with mental health problems are victims of what some might view as an impending ‘cultural collapse’. I’ve always held the view that the ultimate priority should be fixing the underlying problems, not masking the symptoms. So, if the ‘canary in a coal mine’ hypothesis is correct, what could be causing the degradation of balance and harmony in the U.S? I’ve seen fingers pointed at many different elements in society, ranging from stress to technology to consumerism. Let me know what you think could be behind the rise of anxiety and other mental disorders in the comments! 

Among all of the stigma surrounding mental health, schizophrenia fits right in. People experiencing positive symptoms such as hallucinations and delusions are often labeled as crazy or dangerous; negative symptoms, however, such as lack of motivation and blunted affect can lead those with schizophrenia to also be conceived as lazy or uninterested. Much of this stigma comes from misunderstanding of its symptoms and presentation, but we do not fully understand the underlying causes of this disease either. Even more elusive is the reason behind the age of onset for this disorder, which is between late adolescence and early adulthood. As researchers attempt to find better answers to these questions, improve screening, and offer treatments that do more than just mask symptoms, it will be important to focus on how we view schizophrenia and approach its management. 

Why Schizophrenia Occurs – One Piece of the Puzzle

Like most mental disorders, schizophrenia rises from a combination of biological, environment, and social components. You might have heard about factors such as social isolation or specific genes being risk factors, but the way that the messaging systems inside of our cells communicate can have significant impacts on schizophrenia as well. One particular signaling pathway, the Wnt signaling pathway, has been suggested through different lines of evidence to play a part in the development of schizophrenia. The Wnt signaling pathways have a wide range of roles, but are generally involved in development, including the development of the nervous system. In the canonical Wnt pathway, a protein called GSK3 normally works to lower levels of B-catenin (a protein that helps regulate gene transcription) in the cell by marking them for degradation. When Wnt neurotransmitters bind to receptors of this pathway, they inhibit the activity of GSK3. This means that it would no longer lower levels of B-catenin, ultimately allowing B-catenin to enter the nucleus and mediate gene transcription.  

In schizophrenia, it has been proposed that dopamine can alter this pathway by activating GSK3; this would mean that levels of B-catenin are suppressed and unable to regulate gene transcription as normal. Essentially, too much dopamine signaling and not enough Wnt signaling may be mechanisms of schizophrenia development. Other factors can modulate this pathway too – such as the amount of expression for genes such as DISC1 – and therefore have also been suggested to be involved in this development pathway. 

The Onset of Schizophrenia

Interestingly, symptoms of schizophrenia usually do not appear until around 18 to 25 years old, but reasons why symptoms present around this time are not well established. Onset of schizophrenia in childhood is relatively rare, but there is some agreement among experts that schizophrenia does not present ‘out of the blue’ during late adolescence, like its symptoms can make it seem. Instead, symptoms such as hallucinations or delusions are the result of a buildup of molecular changes that start several years earlier, and eventually progress to psychosis.  

A lot of these molecular changes occurring are related to abnormal brain connectivity; during adolescence there is a major reorganization of connectivity between neurons, so this would in part explain the age of onset that is seen. Researchers have found that the DISC1 gene plays a role in connectivity through a couple of different methods. One of these is through forming dendritic spines- the protein expressed by this DISC1 gene acts as a holding place for a protein called Kal-7, which is a critical component of dendritic spine formation in synaptic plasticity, the physical basis for how our brain forms neural connections and “memories”. 

How to Approach Management of Schizophrenia

Given that we do not yet have a medication that can target the underlying cause of schizophrenia or prevent its development, it’s even more critical that we are careful about how we conceptualize this disorder. For individuals with schizophrenia, receiving the proper treatment and support can turn a prognosis from a person being unable to care for themselves to living a functional and rewarding life, whether in the presence of absence of symptoms. Specifically, though, what should be done? In my view, education is possibly the most important step in creating a strong support system for those with schizophrenia. This includes educating the individual, family members of the individual, and communities as a whole; an active focus on education would not only help the individual feel validated through normalizing their experience, but may help families learn how to help their loved one cope and would overall reduce harmful stigma, of just a few possible benefits. As a society that claims to value those who struggle with mental illness, we must take the steps we can to prove it.

Whether you learned about it in school or from the movies, schizophrenia is known about in pop culture for its wild symptoms. As a schizophrenic, being able to conjure up a person so vividly that they think they are seeing a real person that they can have a conversation with was bound to end up in a movie executives lap at some point. Having hallucinations such as these are part of the “positive” symptoms, or things that have been added on to normal everyday, schizophrenic life. There are also negative symptoms, which are a lack of doing something, such as depression or a lack of facial emotivity. Both of these kinds of symptoms have been hallmarks of the disorder for well over a century, and so treatment has also been experimented on for about as long. 

Lithium (yes, the element, in pill form) has been used as a treatment for schizophrenia since at least the late 19th century. It didn’t become a scientifically-based treatment until 1949, and then took another 20 years to get approval from the FDA. The fact that it wasn’t scientifically recognized didn’t stop it from being an effective treatment well before 1949 though, and amazingly, it is still used to this day as one of the most effective treatments for schizophrenia.

This speaks to one of two things. We as a society have either lagged behind in research and development and haven’t been able to adequately come up with, discover, or create a better treatment than lithium, or we luckily discovered one of the best treatments possible for schizophrenia patients early on (way before a lot of medicinal updates) and so to this day it still works as an adequate treatment option that works well. The truth is closer to the second one, of course we’ve come up with more treatment options; we’ve been able to create synthetic antipsychotics that certainly do their job, all thanks to modern medicine. Lithium however, has stood the test of time, continuing to be one of the most effective, responsive treatments for schizophrenia. 

Wnt signalling, a pathway for gene transcription among other things, is influenced by lithium. Lithium works to inhibit GSK3β, which is one of the principal problems discovered within schizophrenia. Overactive GSK3β means a lessened TCF/LEF-transcription factor output, of which lithium can mediate to increase transcription and alleviate the severity of schizophrenic symptoms. This is the mechanism by which lithium acts, but what are some of the other treatments for lithium, and what makes it so effective?

Drugs that treat schizophrenia are often overlapped with bipolar disorder, because the drugs work for both disorders. Comparing the 4 drugs that are commonly used for both, which include lithium, Valproate, Olanzapine, and Quetiapine, lithium can be found to display several benefits. Effective treatment of schizophrenia can be characterized by the ability to take the drug for as long as possible without the downsides of the side effects outweighing the benefits of the drug itself. When a drug is stopped due to this effect, it’s known as treatment failure. Lithium, when compared to the other 3 drugs here, had the longest treatment failure times. It also appeared to be the most effective treatment to prevent relapse or recurrence of bipolar disorder and may prolong the time before complimentary prescribing is necessary.

On that note, a meta-analysis was done on 20 different studies that looked at the effectiveness of lithium and found that as a sole agent, lithium wasn’t as effective as when prescribed with another drug for treating schizophrenia. This is referred to as lithium augmentation, and although some sources disagree, most confirm that this method is the best way to treat either of these disorders. 

There are almost no other drugs that can be said to have been the most effective drug for a disorder for over 150 years, but lithium is in that category.