Memory Suppressor That May Play a Role in Autism Identified

Discovered only in the 1990s, microRNAs are short molecules that work within virtually all cells. Typically, each one functions as a “dimmer switch” for the expression of one or more genes, regulating a wide variety of cellular processes, including learning and memory.

In a new study published in the February 11, 2016 issue of the journal Cell Reports, scientists from the Florida campus of The Scripps Research Institute (TSRI), working in collaboration with scientists from the University of California, Irvine, show that one specific microRNA has strong links to a number of neuropsychiatric disorders, including autism spectrum disorder.

The microRNA, known miR-980, serves as a memory suppressor in multiple brain regions of Drosophila, the common fruit fly, a widely recognized substitute for human memory studies.

“We wanted to know what happens to behavior when we change the levels of these microRNAs,” said Ron Davis, chair of TSRI’s Department of Neuroscience. “When we reduced the level of miR-980, the flies had better memory–that’s something new and surprising.”

Davis noted that this specific microRNA regulates neuronal excitability–the nerve’s capacity for firing–and inhibiting it increased both memory acquisition and stability.

Image shows a DNA strand.
The researchers found that miR-980 targets and inhibits a gene known as A2bp1. This gene previously had been shown to be involved in susceptibility to autism. In addition, it works to promote memory. Image is for illustrative purposes only.

Next, Davis and his colleagues tried to uncover which genes miR-980 regulates, identifying 95 specific targets that might fit that bill. Intriguingly, they found that miR-980 targets and inhibits a gene known as A2bp1. This gene previously had been shown to be involved in susceptibility to autism. In addition, it works to promote memory.

“A2bp1 has been shown to be associated with autism spectrum disorder in humans,” said Research Associate Germain Busto, co-first author of the study with Research Associate Tugba Guven-Ozkan. “We discovered that when A2bp1 was overexpressed, it improved memory and that miR-980 also affected memory when artificially modulated. This offers a powerful model describing the gene network potentially underlying autism spectrum disorder.”

“Linking this microRNA to a disease-linked gene may help us to uncover even more nervous system dysfunctions,” added Guven-Ozkan.

Davis speculated that the different neuronal networks that form due to varying levels of A2bp1 may account for the range of intellectual abilities observed in autism spectrum disorder in the fly model.

“But the fact that A2bp1 plays an influential role in autism and epilepsy in people brings a real human connection to the study,” Davis said. “It’s very exciting.”

About this Autism research

In addition to Davis, Busto and Guven-Ozkan, other authors of the study, “MiR-980 is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1,” are Isaac Cervantes-Sandoval of TSRI and Soleil S. Schutte and Diane K. O’Dowd of the University of California, Irvine.

Funding: This study was supported the NIH.

Source: Eric Sauter – Scripps Research Institute
Image Source: The image is in the public domain.
Original Research: Full open access research for “MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1” by Tugba Guven-Ozkan, Germain U. Busto, Soleil S. Schutte, Isaac Cervantes-Sandoval, Diane K. O’Dowd, and Ronald L. Davis in Cell Reports. Published online February 11 2016 doi:10.1016/j.celrep.2016.01.040


Abstract

MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1

Highlights
•Drosophila miR-980 inhibition enhances olfactory memory; miR-980 overexpression impairs olfactory memory
•miR-980 inhibition in multiple areas of the adult brain enhances memory
•miR-980 modulates odor-induced calcium responses and excitability in the adult brain
•miR-980 represses A2bp1 expression in the adult brain; reducing A2bp1 expression reverses the memory enhancement due to miR-980 inhibition

Summary
MicroRNAs have been associated with many different biological functions, but little is known about their roles in conditioned behavior. We demonstrate that Drosophila miR-980 is a memory suppressor gene functioning in multiple regions of the adult brain. Memory acquisition and stability were both increased by miR-980 inhibition. Whole cell recordings and functional imaging experiments indicated that miR-980 regulates neuronal excitability. We identified the autism susceptibility gene, A2bp1, as an mRNA target for miR-980. A2bp1 levels varied inversely with miR-980 expression; memory performance was directly related to A2bp1 levels. In addition, A2bp1 knockdown reversed the memory gains produced by miR-980 inhibition, consistent with A2bp1 being a downstream target of miR-980 responsible for the memory phenotypes. Our results indicate that miR-980 represses A2bp1 expression to tune the excitable state of neurons, and the overall state of excitability translates to memory impairment or improvement.

“MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1” by Tugba Guven-Ozkan, Germain U. Busto, Soleil S. Schutte, Isaac Cervantes-Sandoval, Diane K. O’Dowd, and Ronald L. Davis in Cell Reports. Published online February 11 2016 doi:10.1016/j.celrep.2016.01.040

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