*This work is part of the IKUR initiative of the Basque Country Government.
“A complex system of small networks”. That could be a definition of how the brain works; several regions work simultaneously, in different ways, but coordinated, to create our memories, to write this manuscript, to decide what to have for dinner, or to fall in love.
But what happens when one brain region malfunctions? Or when the pathways connecting different regions shrink, or their surface deteriorates? This is what occurs in schizophrenia, one of the most burdensome diseases for both patients and their loved ones. It is also one of the most stigmatized conditions of the 21st century. Books, movies, and the media have helped create the misconception of violence and craziness that hardly matches reality. While these patients are not usually violent, they have a 2 to 3 times higher risk of dying prematurely, and their employment rates and annual income are significantly lower. In addition to the positive symptoms like delusions, hallucinations, or disorganized thinking, these individuals also experience negative symptoms such as lack of motivation, social withdrawal, or reduced emotional expression, as well as cognitive issues like attention and memory deficits. All of these profoundly affect their daily lives.
Despite one out of 300 people suffering from schizophrenia, according to the WHO, we are still far from understanding its causes and all the underlying mechanisms involved. The current treatment focuses on managing symptoms with antipsychotics and various behavioral therapies or rehabilitations. Unfortunately, antipsychotics may have harmful side effects, and there is an urgent need for new treatments. However, to achieve this, it is necessary to understand how the brain architecture differs in a schizophrenic patient.
Among the several brain regions affected, one of the main ones is the Prefrontal Cortex, responsible for our rational thinking. This area receives and filters all sensory, memory, and emotional information, transforming it into working memory, decision-making, or goal-focused behavior. To perform these tasks, the prefrontal cortex is finely tuned and tightly regulated to maintain homeostatic excitation/inhibition balance. In schizophrenia, this equilibrium is lost. This leads to a reduction of prefrontal cortex inhibition, impairing its function, information filtering, and connection with other areas, and eventually to the cognitive impairment described. Indeed, this cognitive impairment, characterized in schizophrenic patients, can be observed from early childhood.
Studies have shown that there is a decrease in the quantity and function of parvalbumin neurons, the main inhibitory neurons in the Prefrontal Cortex, observed in schizophrenic patients. Several approaches are being used to characterize how these cells contribute to schizophrenia, and whether its deficit is a cause or consequence of other brain architecture changes. Several studies are ongoing nowadays, from postmortem human studies to in vitro studies, among different mouse studies that include transgenic mouse models or cell modulation via chemo and optogenetics. In general, reducing or inhibiting parvalbumin neurons in the prefrontal cortex of mice led to the cognitive and social deficits observed in human patients. However, many questions remain unanswered before we can translate this into a clinical treatment. How are the other brain areas involved? When does this impairment happen? How can we target these cells in patients? Or, even going back to the basics, are these changes equal in men and women?
Despite its difficulties, many breakthroughs have been achieved in the last decades, and with the needed funding, new treatments will arrive soon. Not only for schizophrenia but also for many other disorders that share common pathologic pathways, such as anxiety or depression. Research is the main way to help our society.
References
- Liu, Y., Ouyang, P., Zheng, Y., Mi, L., Zhao, J., Ning, Y., & Guo, W. (2021). A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms. Frontiers in cell and developmental biology, 9, 664535. https://doi.org/10.3389/fcell.2021.664535
- Marín O. (2024). Parvalbumin interneuron deficits in schizophrenia. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 82, 44–52. https://doi.org/10.1016/j.euroneuro.2024.02.010
Postdoctoral Researcher at the Laboratory of Cellular Basis of Behavior and Disease. Achucarro Basque Center for Neuroscience.