Desiree Lano
Introduction
There’s no denying it: Schizophrenia (SZ) is one of the most misunderstood psychiatric illnesses in our society. Most have had little exposure to it outside of sensationalized media, which often perpetuates it as something to be afraid of. Those with psychiatric illnesses, however, are more likely to be a victim of violence rather than a perpetrator (Ghiasi et al., 2023). In general, society has made adequate progress towards destigmatizing more common mental illnesses, but severe disorders (e.g., bipolar disorder and SZ) have been left out of the equation. Using biology, we can begin to demystify what seems frightening, and help push society towards a truly destigmatized view of mental illness. SZ is a highly complex disorder, with environmental and biological interactions contributing to the manifestation of distressing symptoms. This article will focus on the biological contributions, but it is important to keep in mind that these mechanisms do not act alone.
Signs and Symptoms of Schizophrenia
Signs and symptoms of SZ go beyond hallucinations and are often lumped into three categories: positive, negative, and cognitive symptoms (Klein et al., 2018). Positive symptoms include hallucinations, delusions, loose associations/lack of logical flow of thoughts, disorganized speech, and odd mannerisms. Negative symptoms can consist of blunt affect, catatonia, anhedonia, social isolation, and problems keeping up with activities of daily living. Cognitive symptoms include issues with learning, memory, and executive functioning (McCutcheon et al., 2020). These signs and symptoms just scratch the surface–beyond the clinical criteria, the subjective experience and outward manifestations of SZ are no doubt a frightening experience and cannot be understated.
Cellular/Molecular Mechanisms
Genetics
SZ is a polygenic (i.e., multiple genes contributing rather than a single deterministic gene) disorder with a heritability range of 65-85%. Almost 100 genes have been theorized to contribute to the development of SZ. A major area of interest in SZ research revolves around copy number variations (CNVs). Copy number variations are modifications of small sections of DNA, which can have effects ranging from small to unnoticed to life-threatening (Marshall et al., 2016). A significantly greater amount of rare shortened CNVs have been found in those with SZ using genome-wide studies. It is thought that CNVs contribute to at least 10% of the risk of developing SZ (Zigmond et al., 2023).
Dopamine Dysregulation
A number of neurotransmitters (molecules that carry “messages” between neurons) have been implicated in the dysfunction of cellular communication in those with SZ. A proposed culprit in SZ is one often touted as the “feel-good” chemical: dopamine. Dopamine’s role in the nervous system goes beyond feeling good; it is involved in a multitude of processes in the nervous system, both healthy and diseased. Its involvement in our brain’s “reward system” is familiar to most, but it also modulates movement/motor control, arousal, sleep, attention, affect, cognition, reproductive/maternal behaviors…the list goes on (Klein et al., 2018).
Suffice it to say that dopamine is more than just a feel good molecule–we need it to stay alive and well. Our need for this molecular messenger runs the gamut, from seeking out food, to keeping ourselves satiated, to making purposeful and fluid movements. Dopamine has a particular modus operandi when it comes to SZ. While in the healthy brain dopamine shines the spotlight on important information we should be focusing on, it seems to extend its range to unimportant stimuli in the brain of those with SZ. This often manifests in delusional symptoms for those with SZ, attributing mundane occurrences to an infallible belief of being persecuted or receiving important messages via songs, tv, etc.
Zooming in at the molecular level, brains of those with SZ have been found to have a higher density of D2 dopamine receptors compared to healthy controls (Klein et al., 2018). Interestingly enough, it has been found that D1 dopamine receptors have lower expression in those with SZ, particularly in the prefrontal cortex. This has been proposed to contribute to some of the cognitive deficits associated with SZ.
Reduced Dendritic Spine Density, Plasticity, and Arborization
Dendrites are the “receiving end” of our neurons– these branchlike outgrowths house receptors which receive neurotransmitters via little packets called vesicles. These “receiving” portions of neurons are very important as it is where incoming neural transmission occurs. One of the clearest pathologies seen in those with SZ is the reduction of dendritic spine density (Moyer et al 2015). Using golgi staining and immunohistochemical techniques, multiple studies have shown significant reduction in those with SZ compared to controls. It is important to note that this does not appear to be related to antipsychotic use–in animal models, there were no significant changes in dendritic spine density when antipsychotics were administered over a period of months to one year (Moyer et al., 2015).
There is also evidence for reduced lengths and less arborization (branching) of dendritic spines in SZ. Consequently, this reduced arborization hinders proper neuroplasticity, which has been found to occur in the brains of those with SZ (Moyer et al., 2015). MAP-IR (an important part of the plasticity process) has been also shown to be at reduced levels in SZ. Branching of dendritic outgrowths is important for the process of neuroplasticity, wherein we have the capacity to learn and make new connections between neurons.
It is unclear how dendritic abnormalities contribute to the development and ongoing symptoms of schizophrenia. Perhaps these abnormalities contribute to the cognitive deficits seen in those with SZ. It is important, however, for researchers and clinicians to disentangle difficulties with cognition in those with SZ due to the disease compared to use with the negative side effects of antipsychotics.
Conclusion
Schizophrenia is a heavy burden to bear for those living with it and those around them. There are many physiological abnormalities at play, making it difficult to nail down a cohesive theory and subsequent treatment. Though we may be far from understanding it completely, it is important to remember that people suffering should be treated with the same respect as anyone else. We all have the same parts, just different wiring.
References
Klein, M. O., Battagello, D. S., Cardoso, A. R., Hauser, D. N., Bittencourt, J. C., & Correa, R. G. (2018). Dopamine: Functions, signaling, and association with neurological diseases. Cellular and Molecular Neurobiology, 39(1), 31–59. https://doi.org/10.1007/s10571-018-0632-3
Ghiasi, N., Azhar, Y., & Singh, J. (n.d.). Psychiatric illness and criminality. National Center for Biotechnology Information. https://pubmed.ncbi.nlm.nih.gov/30725749/.
McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An Overview. JAMA Psychiatry. 2020;77(2):201–210. doi:10.1001/jamapsychiatry.2019.3360.
Marshall, C. R., Howrigan, D. P., Merico, D., Thiruvahindrapuram, B., Wu, W., Greer, D. S., Antaki, D., Shetty, A., Holmans, P. A., Pinto, D., Gujral, M., Brandler, W. M., Malhotra, D., Wang, Z., Fajarado, K. V. F., Maile, M. S., Ripke, S., Agartz, I., Albus, M., … Sebat, J. (2016, November 21). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature News. https://www.nature.com/articles/ng.3725.
Zigmond, M. J., Wiley, C. A., & Chesselet, M.-F. (2023). Neurobiology of brain disorders: Biological basis of neurological and psychiatric disorders. Academic Press, an imprint of Elsevier.
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