Science has proven the strong genetic component to schizophrenia, a mental illness that can be severely debilitating, but many questions remain about which genes may cause brain circuitry to malfunction, and how. With the support of a Brain & Behavior Research Foundation NARSAD Distinguished Investigator Grant, Maria Karayiorgou, M.D. and Columbia University colleagues showed for the first time that alterations in the formation of gene-regulators called “microRNAs” in the brain that result from a genetic abnormality lead to schizophrenia-like behavioral and cognitive defects. Their findings offer important new treatment targets for schizophrenia and were published Jan. 17, 2013 in Cell.
The highest known genetic factor in schizophrenia is what is known as 22q11.2 deletion syndrome. Dr. Karayiorgou and team hypothesized that a better understanding of how the genes disrupted by the 22q11.2 deletion contribute to the behavioral and cognitive symptoms of schizophrenia would provide important insights about other genetic contributors to the illness. The team focused on identifying key genes affected by the abnormal microRNA (miRNA) expression resulting from the 22q11.2 deletion syndrome.
“By generating and studying a mouse model for the 22q11.2 microdeletion, we were able to show that the 22q11.2 microdeletion results in abnormal processing of brain miRNAs, implicating for the first time miRNA dysregulation in the pathogenesis of psychiatric disorders and cognitive dysfunction,” explains Dr. Karayiorgou, Columbia University Professor and Acting Chief of the Division of Psychiatric & Medical Genetics, NY State Psychiatric Institute. “By comparing gene expression profiles over three developmental stages and three levels of genomic dosage at the 22q11.2 locus, we identified elevated levels of a previously uncharacterized gene, Mirta22, as the most robust change in gene expression and the key target of miRNA dysregulation resulting from the 22q11.2 microdeletion.”
Mirta22 is a gene that is expressed prenatally, suggesting that it could play an important role in both restricting neural circuit formation prenatally and neuronal maturation and synaptogenesis in the postnatal brain. “Targeting Mirta22 offers a new opportunity towards development of drugs for psychiatric and cognitive disorders focused on targeting inhibitors of neuronal connectivity and in this way promoting formation of neuronal connections in the diseased brain and facilitating neuronal communication,” says Dr. Karayiorgou.