Schizophrenia is a chronic mental illness that alters a person’s thinking, perception, and behavior. It affects approximately 0.3% to 0.7% of the population worldwide. Understanding the biological mechanisms of this disorder requires examining its pathophysiology. These changes involve disruptions across multiple biological systems, including the brain’s chemical messaging, its physical structure, and developmental processes, all rooted in a complex genetic foundation.
Imbalances in Brain Chemistry
The symptoms of schizophrenia, such as hallucinations and disorganized thought, are linked to disturbances in the brain’s chemical communication, particularly involving key neurotransmitters. The oldest theory focuses on dopamine, which is involved in motivation, reward, and movement. This theory suggests that over-activity of dopamine signaling in specific brain pathways, particularly the mesolimbic pathway, contributes directly to “positive symptoms” like delusions and hallucinations.
The effectiveness of older antipsychotic medications, which block dopamine D2 receptors, supports the concept of dopamine hyper-function. The hypothesis has been refined to suggest a nuanced imbalance: excessive dopamine activity in one area coexists with reduced function in others. Specifically, hypo-function of dopamine in the mesocortical pathway is thought to contribute to “negative symptoms,” including blunted emotions and social withdrawal.
A more modern view integrates the role of glutamate, the brain’s main excitatory neurotransmitter. The glutamate hypothesis centers on the N-methyl-D-aspartate (NMDA) receptor. Reduced function of these NMDA receptors is thought to lead to widespread disorganization in neural circuits.
This dysfunction may be a primary driver of cognitive impairment and negative symptoms. Furthermore, a lack of glutamate activity in the prefrontal cortex can lead to the observed over-activity of dopamine in the striatum, creating a unified model where glutamate hypofunction drives the subsequent dopamine imbalance.
Structural Differences in the Brain
Schizophrenia is consistently associated with measurable structural differences in the brain. A highly replicated finding in neuroimaging studies is the enlargement of the cerebral ventricles, which are fluid-filled spaces. This enlargement is understood to be a consequence of a corresponding reduction in brain tissue volume, rather than an increase in fluid.
This tissue loss primarily manifests as a reduced volume of cortical gray matter, which contains neuron cell bodies. The reduction is particularly noticeable in regions like the prefrontal cortex and parts of the temporal lobe. These areas are involved in higher-order functions like decision-making, memory, and emotional processing, aligning with the cognitive and emotional difficulties experienced by individuals with the disorder.
The gray matter volume reduction appears progressive and is linked to the expansion of the ventricles. Additionally, the brain’s internal wiring, composed of white matter tracts, shows abnormalities. These deficits disrupt efficient communication between various brain areas, leading to impaired functional connectivity and contributing to the fragmented thought processes characteristic of schizophrenia.
The Role of Genetics and Heredity
Schizophrenia has a substantial genetic component, indicating that a predisposition for the disorder can be passed down through families. Studies involving twins and first-degree relatives estimate the heritability of schizophrenia to be high, falling between 70% and 85%. This indicates a strong inherited risk.
Schizophrenia is not caused by a single gene but is a polygenic disorder, meaning hundreds of common genetic variations each contribute a small amount to the overall risk. These small effects combine to create an individual’s total genetic liability, often quantified as a polygenic risk score. The genes implicated often converge on pathways related to neural signaling and brain development, linking genetics to the observed chemical and structural abnormalities.
Genetic predisposition alone is typically not enough to cause the disorder; it requires interaction with environmental factors. Genetic vulnerability serves as an underlying sensitivity that can be triggered or amplified by specific external influences, such as early life stress, infections, or complications during birth. The interplay between inherited risk and environmental exposures ultimately determines whether the disorder manifests.
Schizophrenia as a Developmental Disorder
Schizophrenia is framed as a neurodevelopmental disorder, where pathology begins early in life, long before symptoms appear. Prenatal and perinatal risk factors, such as maternal infection or obstetric complications, can subtly disrupt early brain formation. This early disturbance establishes a latent vulnerability that persists throughout childhood.
The emergence of psychotic symptoms often aligns with brain maturation in adolescence and early adulthood. During this time, the brain undergoes synaptic pruning, the selective elimination of weak neural connections to increase efficiency. In individuals who develop schizophrenia, this pruning process is hypothesized to be excessive or dysregulated, particularly in the prefrontal cortex.
Specific genetic findings, such as risk variants in the C4 gene, suggest a mechanism for this excessive pruning involving the immune system’s complement cascade, which tags synapses for removal. This faulty elimination of connections reveals the physiological vulnerability established years earlier, leading to the cognitive and perceptual deficits that define the disorder. The observed structural and chemical abnormalities are the result of a long-term deviation from the typical trajectory of brain development, culminating in clinical onset in young adulthood.