Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys": master regulators at the center of a gene network that is important for brain function. In a study published today in Nature Neuroscience, researchers created mice partially lacking one of those master keys, MIR-137, and have used them to identify a potential treatment option for ASD.
MIR-137 encodes a microRNA that regulates hundreds of other genes, and having just the right level of MIR-137 function is important. Previous studies of people with genetic deletions show that a loss of MIR-137 is connected with intellectual disability and autism spectrum disorder. The reverse situation, in which a genetic variation increases MIR-137 levels, appears to contribute to schizophrenia.
"Several studies had shown an association between MIR-137 and both ASD and schizophrenia, but it was very important to show that causal relationship," says senior author Peng Jin of Emory University.
According to Jin, generating mice with a heritable disruption of MIR-137 was technically challenging. Mice completely lacking MIR-137 have problems with development and die soon after birth. The effect is similar if the deletion is restricted to the nervous system. Other "knockouts" of microRNA genes have not displayed such distinct post-natal effects, Jin notes. However, the scientists wanted to study animals that had one copy intact—a situation analogous to humans with ASD.
Mice lacking one copy of MIR-137 display learning and memory deficits, repetitive behaviors, and impaired sociability. The brains of mutant mice have a higher density of dendritic spines, indicating that they have impaired synaptic pruning, a process that other researchers have observed to be altered in schizophrenia and autism.
Analyzing the genes in brain cells whose activities were most altered by the loss of MIR-137 allowed the researchers to pinpoint the enzyme phosphodiesterase 10a (Pde10a), which is elevated in mutant mice. Treating mutant mice with papaverine, a Pde10a inhibitor, significantly increased the amount of time mutant mice spent interacting with other mice and improved their ability to learn mazes, though not to the level of control mice.