A gene linked to schizophrenia? New insights and new models for the devastating disorder.

or technically,

Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation.

[See Original Abstract on Pubmed]

Authors of the study: David J. Tischfield, Dave K. Saraswat, Andrew Furash, Stephen C. Fowler, Marc V. Fuccillo, Stewart A. Anderson

Hallucinations, delusions, and paranoia. Agitation, depression, and trouble sleeping. The symptoms of schizophrenia vary from person to person, but one fact remains the same: there is currently no known cure for the disorder that affects over 77 million people worldwide. Due in large part to its incredibly diverse set of symptoms, schizophrenia is an extremely challenging disorder to study. David Tischfield, a neuroscience graduate student working in the laboratory of Dr. Stewart Anderson at the University of Pennsylvania, tackled this problem by studying the relationship between a recently identified neurodevelopmental geneA unit of DNA that encodes a protein and tells a cell how to function and its contribution to normal and abnormal brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function.

Thanks to recent advancements in technology, scientists have been able to identify genesA unit of DNA that encodes a protein and tells a cell how to function that are associated with all sorts of diseases and disorders. Two such studies1,2 have linked ZSWIM6, a geneA unit of DNA that encodes a protein and tells a cell how to function of unknown function, to schizophrenia and other severe neurodevelopmental disordersA disorder in which the development of the central nervous system is disturbed, which often leads to neuropsychiatric problems or impaired function. Building off of these previous studies, David sought to characterize this geneA unit of DNA that encodes a protein and tells a cell how to function in mice and determine its role in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development and disease.

Based on studies performed in humans, we know that patients with schizophrenia often have abnormalities in a part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. called the striatumA region in the front of the brain that is critical for motor and reward system - a region that plays a role in regulating voluntary movements. This makes sense as many symptoms of schizophrenia are movement-based: agitation, repetitive movements, lack of restraint, impaired coordination, etc. Interestingly, Zswim6 (the proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. encoded by the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function in mice) is present in very high levels in this region. David therefore wondered if Zswim6 dysfunction in the striatumA region in the front of the brain that is critical for motor and reward system, specifically, could cause developmental brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. abnormalities that could explain some of the symptoms of schizophrenia. To test this, he deleted this geneA unit of DNA that encodes a protein and tells a cell how to function in a group of mice, and then compared the behaviors and brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development of mice with and without Zswim6.

In terms of neurodevelopment, David found that mice lacking Zswim6 had smaller striata than the mice who had normal levels of Zswim6. In line with this, the mice lacking Zswim6 also had a reduced number of medium spiny neuronsA special type of cell located in the human striatum, especially important in the transmission of dopamine. (the main type of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cell that makes up the striatumA region in the front of the brain that is critical for motor and reward system), as well as significant abnormalities in the structure of these cells. David then performed behavioral experiments on the mice lacking Zswim6 to determine if there were any changes in motor learning and overall behavioral control (remember: the striatumA region in the front of the brain that is critical for motor and reward system is important for regulating movements). Indeed, David found that the mice lacking Zswim6 did show differences in movement-related behavior. Not only did they have a harder time balancing on a rotating "treadmill" of sorts, but the mice without the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function also tended to be a lot more hyperactive (think: sprinting around their cage). This hyperactivity was further increased when the mice were given a low dose of amphetamine (a stimulant drug similar to Adderall that speeds up your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. and your movements). However, this increase in hyperactivity with amphetamine was only seen in the mice lacking Zswim6 - low doses of the drug had no effect on regular mice. This finding is important as extreme sensitivity to amphetamines is a common symptom in humans suffering from schizophrenia, and these drugs can actually induce psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways in those who take them. Therefore, this result further links Zswim6 to specific aspects of schizophrenia.

David’s work not only gives us more information about an important geneA unit of DNA that encodes a protein and tells a cell how to function that we previously knew nothing about, but it also provides the field with a new mouse model, the Zswim6 “deleted” mice, that could be extremely useful in future studies of schizophrenia and its related disorders. In particular, this model reproduces the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region abnormalities, movement problems, and hypersensitivity to amphetamines that are seen in humans with schizophrenia. As schizophrenia is chronic, debilitating, and currently without cure, finding effective ways to study it are of the utmost importance. David’s work leads the way towards understanding the science behind such misunderstood and devastating disorders.
About the brief writer: Kelsey Nemec  As a 2nd year NGG student, Kelsey is interested in using neural stem cells to study neurodevelopment and neurodegeneration in various diseases and disorders.

About the brief writer: Kelsey Nemec

As a 2nd year NGG student, Kelsey is interested in using neural stem cells to study neurodevelopment and neurodegeneration in various diseases and disorders.

Citations:

  1. Ripke, S., et al., 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45:1150–1159. Read it here

  2. Schizophrenia Working Group of the Psychiatric Genomics, C, 2014,. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Read it here.

Want to learn more about how researchers study neurodevelopmental disorders like schizophrenia? You can find David’s full paper here!