High miR-101a Levels May Underlie Processes Leading to Rett Symptoms
Small RNA molecule was expressed at elevated levels in hippocampus of Rett mice
Levels of a small RNA molecule called miR-101a may be elevated in certain brain regions of people with Rett syndrome, according to a preclinical study.
The data suggest that higher miR-101a levels can alter signals sent by nerve cells, which may impair normal brain circuitry to contribute to the development of Rett symptoms.
The study, “MeCP2 loss-of-function dysregulates microRNAs regionally and disrupts excitatory/inhibitory synaptic transmission balance,” was published in the journal Hippocampus.
Rett syndrome is chiefly caused by mutations in the gene MECP2. These mutations are broadly known to cause abnormalities in brain development, but the specific biological mechanisms remain incompletely understood.
When a gene is “read” to make protein, the genetic code is copied into a temporary molecule called messenger RNA, which is used as a template by the cell’s protein-making machines called ribosomes. MicroRNAs (miRNA), as the name suggests, are small RNA molecules that do not code for proteins — but they can play key roles in regulating a cell’s genetic activity by interacting with protein-coding messenger RNAs.
In the new study, a quartet of U.S. scientists conducted an analysis to identify microRNAs that are dysregulated by MECP2 mutations.
The team first analyzed data collected in several previous studies done in a mouse model of Rett, and they identified 10 miRNAs that were expressed at altered levels in Rett syndrome. Four of these miRNAs — named miR-101a, miR-137, miR-140, and miR-203 — have been previously suggested as important for the development of nerve cells and the maintenance of synapses (the connections between neurons).
miR-101a was found expressed at elevated levels in the hippocampus
The team examined levels of these miRNAs in different brain regions from Rett mice. Results showed that, compared to control animals, miR-101a was expressed at elevated levels in the hippocampus — a part of the brain with a central role in regulating memory — while miR-203 was upregulated in the cortex, which is involved in higher-level cognition. The other two miRNAs were present at similar levels in Rett and non-Rett animals in the hippocampus and cortex.
“While we cannot rule out altered expression of these genes in other brain regions, we focused on miR-101a and miR-203 in the hippocampus and cortex, respectively,” the scientists wrote.
In further tests, the researchers engineered nerve cells to express higher-than-normal levels of miR-101a or miR-203, and then assessed the electrical activity of the cells.
Results showed that increasing miR-101a levels boosted the overall strength of excitatory transmissions — signals that prompt neurons to “fire” — while simultaneously reducing inhibitory signals that prevent cells from firing. Overexpressing miR-203, by contrast, did not affect electrical activity.
“Because miR-101a [overexpression] led to opposing effects on excitatory and inhibitory spontaneous neurotransmission, and miR-101a is upregulated in MeCP2 [knockout] hippocampus, we concluded that miR-101a may be a key downstream effector of MeCP2 in the hippocampus,” the researchers wrote.
More detailed analyses showed that overexpressing miR-101a increased the release of inhibitory signals from nerve cells, while it did not affect the number of inhibitory synapses. By contrast, this overexpression increased the number of excitatory synapses, but did not change the rate of individual signals being sent.
“Importantly, miR-101a influenced synaptic phenotypes [characteristics] at both excitatory and inhibitory synapses in disparate ways. These results suggest that a single miRNA which is dysregulated in MeCP2 loss of function conditions can be responsible for broad synaptic dysfunction in a specific brain region,” the researchers concluded.
The team postulated that altered inhibitory and excitatory signaling could lead to differences in the brain’s circuitry that ultimately give rise to behavioral differences and other symptoms of Rett, though they stressed a need for further research into the specific abnormalities linking small RNA molecules to symptoms.
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