The Brain's Careful Construction of Reality: The Mechanisms Behind Schizophrenia (by Danielle Steinbach)
Aug 16, 2025By Danielle Steinbach
In 1810, apothecary John Haslam published Illustrations of Madness and described the struggles of his patient James Tilly Matthews and his mysterious psychological condition.
Matthews was a patient at the Bedlam psychiatric ward in London who had been detained and imprisoned within the walls of the mental institution after harassing a nobleman in a government building.
When John Haslam was assigned to observe Matthews in Bedlam, he would discover that there was more to Matthews and his psychology than simple aggression issues.
Upon a series of interviews with Haslam, Matthews would begin to unveil a treacherous political plot being carried out by a band of rebels trying to promote the Jacobin’s revolutionary overthrow of the French government. He warned Haslam that these subversive actors had constructed a powerful device called an “Air Loom”, which harnessed magnetic waves to control his mind and send unbidden thoughts called ‘brain-sayings’ into his head.
Despite being held down by manacles during his retention in Bedlam, Matthews relentlessly declared to Dr. Haslam the great danger these rebels and their mind-control device posed to the British government by trying to install Jacobin enemies in the French government.
Never having encountered such a severe severance from reality in a patient, Haslam believed that Matthews was suffering from an acute form of paranoia and psychosis that he called “premature dementia”.
Nearly a century later, Matthews’ condition would come to be known as something else entirely.
Schizophrenia.
A disorder first named by psychiatrist Eugen Bleuler, schizophrenia is characterized by a series of symptoms, including sensory hallucinations, moments of confusion, incoherent speech, alogia (a lack of speech), and anhedonia (a lack of pleasure). These are some of the many symptoms that characterize schizophrenia.
Even to this day, researchers scramble to pinpoint what drives this condition and the distortion of life that comes with it.
Through the genetics revolution and the statistical power of GWAS studies, researchers have been able to identify a myriad of single nucleotide polymorphisms (SNPs) – one-base changes in the DNA sequence – that are highly co-correlated with schizophrenia. Among these SNPs is one that occurs in the GRIN2A gene, which codes for a protein component of glutamate receptors in neuronal cell membranes. In receptor-molecule interactions, the shape of the protein components within the receptor is critical to allow for the correct lock-key interaction between the receptor and the substance binding to it (the ligand). Malformations in the protein structure of glutamate receptor proteins could therefore alter the receptor’s shape enough to prevent glutamate from binding to its receptor on postsynaptic neurons. The possibility of a GRIN2A SNP contributing to the genesis of schizophrenia thus suggests that root cause of schizophrenia could be insufficient excitation within the brain. If this were the case, a critical next step to treating schizophrenia would be localizing where in the brain these malformed glutamate receptors are being expressed (given that not all cells express the same surface-level receptor proteins). In identifying where this structural difference occurs in the brains of schizophrenic patients, physicians and researchers can selectively target that specific brain region with drugs or non-invasive magnetic stimulation therapies like transcranial magnetic stimulation (TMS).
An additional clue pointing towards the role of glutamate in schizophrenia is the prevalence of DTNBP1 mutations in patients with this condition. The DTNBP1 gene is involved in development of the NMDA class of glutamate receptors and thus also allows for regulation of the glutamate circuit in the brain.
In the search for genes that play an insidious factor in schizophrenia, researchers have also identified the NRG1 gene, which plays a crucial role in promoting myelination within the central nervous system. Myelin sheaths are insulators wrapped around the axons of neurons that expedite the “jumping” of electrical signals along the axons. In other words, myelin allows for efficient processing and transfer of information within the brain, particularly in sensory regions like the cerebral cortex. Without myelin, there could be an endless number of impacts on one’s sensory perception and understanding of reality – it’s entirely possible these symptoms could be as severe as the sensory mismatch seen in schizophrenia.
Another SNP that tends to co-occur with schizophrenia may seem less obvious in how it contributes to the development of the pathology: the STAG1 mutation. When identical chromosomes pair together during mitosis and migrate towards the center of the cell, metaphase is initiated and the chromosome pairs will separate such that each chromosome pair will separate into its own daughter cell. In order for these chromosome pairs to attach to each other, a cohesion complex must bind the chromosomes together. STAG1 encodes for a protein in this cohesion complex and thus becomes a main actor in the correct separation of chromosomes during metaphase. It may seem surprising that a protein involved in such an upstream, critical process as chromosome separation in metaphase would directly impact schizophrenia pathogenesis. However, the location of cohesion complexes and the ability of the chromosomes to properly, completely separate in metaphase determines the ability of daughter cells to express the correct combination of genes needed for proper neuronal development. The combination of genes that could be mis-expressed due to STAG1 mutations remains unclear and presents another mystery for researchers to pursue in resolving schizophrenia.
However, beyond SNPs, a multitude of other genetic variations could occur that result downstream in symptoms of schizophrenia. Genetic deletions – including the 22q11.2, 3q29, 1q21.1 deletions – have been significantly implicated in schizophrenia, leading researchers to further investigate the roles of those genetic sequences that have been eliminated.
Zooming out to look at the physiological markers that define schizophrenia, there are several neurological differences that contribute to the development of this psychosis. Although there are no verified, commonly-used biomarkers of schizophrenia, researchers are in the midst of investigating several neurological changes that could occur with schizophrenia.
The primary area of interest in schizophrenia studies is the thalamus-cerebral cortex network, a system in the brain that constructs our entire conscious reality. The thalamus serves as the central relay hub within the brain, sending raw sensory stimuli signals to the cerebral cortex for higher-order processing. The breakdown of this carefully organized, highly complex system could mark the very degradation of one’s entire grip on reality. The brain has been evolutionarily fine-tuned to perfection, and so there is a frighteningly low tolerance for wrong miswirings or breakdowns in communication.
On the molecular level, researchers have also flagged a curious cell-surface difference between healthy controls and schizophrenic patients. Within the brain, special protector cells called microglia circulate throughout the cortical tissue, prepared to attack any substance deemed toxic or foreign. These microglia are essentially immune cells specialized for the brain. In healthy controls, microglia will express a certain amount of surface proteins called major histocompatibility complexes (MHCs) that allow them to latch onto potential toxins in the brain and incite other immune cells to launch a full-scale attack against the pathogens. Part of this immune response triggered by microglia is inflammation, which can be critical in drawing other microglia to the site of injury or pathogens within the brain. However, when taking a closer look at the microglial protein expression patterns in schizophrenic patients, researchers have found aberrant expression levels of these MHCs. This irregularity serves as a compelling piece of evidence that inappropriate and dysregulated inflammation could be a root cause of cortical dysfunction in schizophrenia.
Switching from the molecular lens to the neurochemical lens, researchers have also found that schizophrenic patients exhibit altered levels of dopamine in the striatum, a region responsible for higher-level processing that impacts planning and social behavior. Researchers have begun to consider whether or not this indicates the striatum as a candidate region that drives hallucinations and social paranoia in schizophrenia.
Clarifying the molecular, genetic, and chemical factors that drive schizophrenia remains an active area of research and a key step in developing therapies to treat this condition that bears the potential to so brutally warp one’s perception of the world around them.
Among the many therapeutics being developed to treat schizophrenia, the most promising ones include cognitive behavioral therapy and second-generation antipsychotic medications like clozapine.
However, before these treatments can be optimized, one must first endeavor to understand the mechanisms that underlie the disease itself. In the complex network of the brain, understanding the root cause of any condition can be a daunting, years-long battle. When the brain plays such a critical role in our perception of reality, there are so many different avenues of research to pursue in the question of what could cause such a distortion of one’s conscious reality.
These are the questions that shape careers and consume scientists.
And so the investigation goes on as researchers probe the brain ever deeper to discover the root causes of schizophrenia.
Someday soon, we may just be able to free millions of people from the brain-sayings of the dreaded Air Loom and bring them back into alignment with the reality of the people they love most.
- Danielle Steinbach
Sources:
https://www.fkawdw.nl/en/review/image/the_unlimited_realm_of_the_limit_objectivity_and_schizophrenia
https://www.scientificamerican.com/article/how-schizophrenias-definition-has-evolved-timeline/
https://mikejay.net/james-tilly-matthews-and-the-air-loom/
https://www.sciencedirect.com/science/article/pii/S0920996423003535
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