Thinking in Circles

Circular RNAs (circRNAs) are a sizable class of RNA that are highly expressed in the brains of mammals, but until recently, scientists were unsure of their purpose. Now, researchers led by Nikolaus Rajewsky have linked a circular RNA to brain function.

Image Credit: The Circular RNA Biology Training Network

In 2013, two groundbreaking studies, one of them by the research team from this study, characterized circular RNAs for the first time. It was at this point that scientists confirmed that circRNAs were not errors-- that they were instead specifically expressed, and conserved throughout evolution. The 2013 research by the Rajewsky team described Cdr1as, a circRNA that acts as a sponge for the microRNA miR-7, a small non-coding RNA molecule involved in regulating gene expression.  They found Cdr1as has more than 60 binding sites for miR-7, although the purpose of the attraction was unknown.

Knockout Mice

In their current work, the team showed that microRNAs miR-7 and miR-671 both bind to Cdr1as, in both mouse and postmortem human brains. They then used CRISPR  in mice to delete the locus and create a mutant strain of Cdr1as-deficient animals. These knockout mice initially appeared to be normal; they were fertile, healthy, and there were no obvious changes in the anatomy of their brains. However, the researchers found changed levels of free microRNA in regions of the brain now devoid of Cdr1as. For example, miR-671 was increased, while miR-7 levels were notably decreased. These changes occurred after transcription, indicating that Cdr1as usually interacts with microRNAs outside of the nucleus, in the cell's cytoplasm.

“This indicates that Cdr1as usually stabilizes or transports miR-7 in neurons by sponging them up, while miR-167 might serve to regulate levels of this particular circular RNA,” Rajewsky said in a statement. He added: “Maybe we should think about Cdr1as not as a 'sponge' but as a 'boat.' It prevents its passengers from drowning and also moves on to new ports.”

The knockout mice also exhibited abnormal neuronal activity and disrupted neurotransmission. Practical behavioral consequences included "disrupted pre-pulse inhibition," expressed as a poor ability to suppress the startle response despite receiving a warning. Similar disruptions in pre-pulse inhibition have been observed in humans with psychiatric diseases, who have difficulty filtering out noise that is of no consequence. Ultimately, these findings may mean new treatments for people with these kinds of psychiatric disorders.

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