Scientists Uncover Potential New Target for Schizophrenia Treatment

By Eric Sauter

Scientists from Scripps Florida, part of The Scripps Research Institute, and colleagues have for the first time linked a specific microRNA to behavioral problems frequently associated with psychiatric disorders such as schizophrenia. The finding presents new opportunities in the development of potential treatments.

The study is being published this week in the Early Edition of the journal Proceedings of the National Academy of Sciences.

Scientists had previously known that a number of brain disorders—including schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), mood disorders, and other psychiatric illnesses can involve a disruption in a signaling process in the brain involving N-methyl-D-aspartate (NMDA) glutamate receptors, which are regulators of rapid neurotransmission and synaptic plasticity—the ability of neuronal connections to change strength. Yet the specific molecular components of this disruption have remained a mystery.

In the new study, however, the research team, led by Scripps Florida Professor Claes Wahlestedt, shed some light on the molecular mechanisms associated with NMDA-related behavior problems in mice. Specifically, the team discovered that disruption of NMDA signaling is associated with a reduction of a non-coding microRNA known as miR-219. Non-coding RNAs are small molecules that do not produce proteins, yet often play a vital role in gene expression.

"In the study we asked the question, 'Which noncoding RNA players might have something to do with NMDA signaling in the prefrontal cortex part of the brain?'" said Wahlestedt. "As we discovered, miRNA-219, which is a brain-specific microRNA, plays an integral part in the NMDA signaling process. Our findings strongly support the idea that this previously uncharacterized microRNA significantly modulates NMDA signaling and associated behavioral problems."

To learn more about the molecular components of these behavior problems, the scientists disrupted NDMA signaling using both pharmacological and genetic methods. For the pharmacological portion of the study, the scientists treated normal mice with dizocilpine, a known NMDA antagonist reported to cause changes in human patients that resemble acute psychosis. For the genetic portion of the study, the scientists studied mice that had a mutation in the gene Grin1, which results in a dramatic decrease in NMDA expression levels. The scientists found that, in both cases of NMDA disruption, levels of miR-219 were reduced in the prefrontal cortex, the area of the brain associated with memory, personality, and decision-making.

Interestingly, pretreatment of the mice with the antipsychotic drugs haloperidol and clozapine prevented the behavioral abnormalities and reduction of miR-219 in both groups.

The scientists went on to shed light on the actions of miR-219 in the NMDA signaling cascade (a chain of reactions where one reaction is consumed by the next). The team found that miR-219 targets a key component of the signaling cascade, specifically, CaMKIIγ, a calcium/calmodulin-dependent protein kinase (kinases are enzymes that add a phosphate group to molecules and are important to signaling). The study showed that miR-219 repressed the levels of the kinase in vitro and that inhibition of miR-219 in vivo altered the expression of CaMKIIγ. Calcium is important in signal transduction pathways, where it helps release neurotransmitters from neurons; calcium flow through NMDA is believed to play a vital role in synaptic plasticity.

"We have shown the involvement of miR-219 in the signaling cascade, and with this important calcium kinase, and that makes miR-219 even more of a target of interest for potential drug development," Wahlestedt said. "These two facts alone mean that we should look at this microRNA far more than we have in the past."

The first author of the study, microRNA-219 Modulates NMDA Receptor Mediated Neurobehavioral Dysfunction, is Jannet Kocerha of The Scripps Research Institute. In addition to Wahlestedt, other authors include Mohammad Ali Faghihi, Miguel A. Lopez-Toledano, Nicole Sales, and Paul J. Kenny of The Scripps Research Institute; Jia Huang of The Scripps Research Institute and the University of Miami; Amy J. Ramsey and Marc G. Caron of Duke University Medical Center; David Willoughby of Ocean Ridge Biosciences; Joacim Elmen, Henrik F. Hansen, and Henrik Orum of Santaris Pharma; and Sakari Kauppinen of Santaris Pharma and the University of Copenhagen.

The study was supported by the National Institutes of Health and the State of Florida.

Send comments to: mikaono[at]scripps.edu

"Our findings strongly support the idea that this previously uncharacterized microRNA significantly modulates NMDA signaling and associated behavioral problems," says Scripps Florida Professor Claes Wahlestedt.