Understanding how mind, brain and behavior are affected in psychiatric disorders is an inherently multilevel and multidisciplinary endeavor.
Joseph Gogos traces the molecular, cellular, synaptic and circuit mechanisms that give rise to schizophrenia. His work is paving the way for new strategies to reverse, or even prevent, this devastating psychiatric disorder.Read more about Joseph A. Gogos, MD, PhD >
More than one in a hundred adults worldwide suffer from schizophrenia. It is a disorder with mysterious origins and stubbornly untreatable symptoms, including problems with mood, memory, and perceptions of reality.
Scientists have worked for decades to crack the case, with only minimal progress. “The only given when we started working on this puzzle was that schizophrenia has strong genetic origins,” says Joseph Gogos, MD, PhD, a neuroscientist and principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute who studies the disease. His lab focuses on the genetics of schizophrenia, and, he says, “Many questions remained unanswered.”
Those questions include: What kind and how many different mutations increase the risk for schizophrenia? What kind of failures in brain circuits lead to its symptoms? Why are conditions such as schizophrenia so frequent? To solve these puzzles, Dr. Gogos studies both human and mouse genetics.
In one important study, he and collaborators analyzed the genomes of over a thousand people. Some had schizophrenia and a family history of the disease, some had schizophrenia with no family history, and some were healthy. The researchers found a collection of rare mutations that were inherited in families with a history of the disease, and another collection of rare mutations that appeared spontaneously in others with the disease.
Dr. Gogos describes his reaction to the result as a “humbling experience”— to see that “schizophrenia is characterized by a great degree of genetic heterogeneity, far greater than we ever anticipated and possibly far greater than any other human disease.” at so-called heterogeneity — in which many genes contribute to the disease — explains schizophrenia’s prevalence, but also raises the question of how such variety can lead to a consistent set of symptoms.
To study the effects of these genes in more detail, Dr. Gogos’ lab creates mouse models of schizophrenia by mutating the same genes in the animals. The research team can then perform observations: monitor the mouse’s behavior, record the activity of individual brain cells as the animal behaves, scan the activity across its entire brain, or even dissect the brain and analyze its circuitry.
In one recent study, Dr. Gogos and his colleagues looked at the hippocampus, a part of the brain that supports memory. In one of the hippocampus’s subregions, called the CA2, mice with a certain set of mutated genes had fewer brain cells called inhibitory neurons, which regulate the activity of surrounding brain cells. Additionally, the mice showed impaired social memory, which is the inability to recognize mice they had previously encountered. Reduced inhibitory neurons and impaired social memory are both common in humans with schizophrenia.
Another set of recent studies looked at how neurons grow branches in the hippocampus and the prefrontal cortex, the area responsible for executive control. The researchers found that a genetic mutation relatively common in schizophrenia results in overactivity of a protein that stunts this branching. They also found that by blocking this protein with a chemical compound in young mice, the branches could grow normally and memory was restored. This work is promising, as it could over new treatment strategies for the underlying mechanisms that lead to memory impairments — one of schizophrenia’s hardest symptoms to address.
At the Zuckerman Institute, Dr. Gogos appreciates working alongside his former postdoctoral advisor, Richard Axel, MD, whose “mesmerizing work,” he says, initially attracted him to neuroscience—as well as with a diverse team of other scientists at the Institute. “Understanding how mind, brain and behavior are affected in psychiatric disorders,” he says, “is an inherently multilevel and multidisciplinary endeavor.”