MicroRNA Protects Normal Brain from Trauma and Stress

A microRNA has been identified that helps prevent the normal brain from becoming susceptible to the type of seizures induced by trauma or stress in individuals with epilepsy.

MicroRNAs (miRNAs) are a small noncoding family of 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

Epilepsy may have genetic or pharmacological origins or may develop following injury. However, it remains unclear how the normal brain escapes susceptibility to seizures.

Investigators at the Hebrew University of Jerusalem (Israel) hypothesized that rapidly inducible microRNAs could mediate such protection. To test this theory, they combined genetic engineering of mouse lines, RNA sequencing, electric recording of brain activity, and learning tests. Specifically, they engineered dTg-211 mice to overproduce a doxycycline-suppressible form of the microRNA miR-211 in their forebrains.

Results published in the June 5, 2017, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences revealed that the genetically engineered mice reacted to doxycycline exposure - which lowered levels of miR-211 - by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating microRNA, miR-134. RNA sequencing of the doxycycline-treated dTg-211 mice showed overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 (transforming growth factor, beta receptor II) signaling, and cholinergic synapse pathways.

"Dynamic changes in the amount of miR-211 in the forebrains of these mice shifted the threshold for spontaneous and pharmacologically induced seizures, alongside changes in the cholinergic pathway genes," said senior author Dr. Hermona Soreq, professor of molecular neuroscience at the Hebrew University of Jerusalem. "It is important to discover how only some people's brains present a susceptibility to seizures, while others do not, even when subjected to these same stressors. In searching for the physiological mechanisms that allow some people's brains to avoid epilepsy, we found that increased levels of micro-RNA 211 could have a protective effect."

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Hebrew University of Jerusalem