Elevated levels of miR-101a may underlie the processes that lead to Rett symptoms | Elevated levels of miR-101a were found in Hippocampus of Rett Mice

Levels of a small RNA molecule called miR-101a may be elevated in certain areas of the brain in affected people Rett syndromeAccording to a preclinical study.

The data suggest that higher levels of miR-101a can alter the signals sent from neurons, which may impair normal brain circuits to contribute to the development of Ret symptoms.

the study, “MeCP2 loss of function leads to regional dysregulation of microRNAs and disrupts the balance of excitatory/inhibitory synaptic transmission.“in the magazine hippocampus.

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Rett syndrome is mainly caused by Through mutations in the gene MECP2. These mutations are widely known to cause abnormalities in brain development, but the specific biological mechanisms are still not fully understood.

When a gene “reads” to make a protein, the genetic code is transcribed into a temporary molecule called messenger RNA, which is used as a template by the cell’s protein-making machinery 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 American scientists conducted an analysis to identify unregulated microRNA molecules by MECP2 mutations.

The team first analyzed data collected in several previous studies in the mouse model of Rett, and identified 10 miRNAs that were expressed at variable levels in Rett syndrome. Four of these microparticles–called miR-101a, miR-137, miR-140, and miR-203–were previously proposed to be important for neuronal development and the maintenance of synapses (the connections between neurons).

miR-101a is found in elevated levels in the hippocampus

The team examined levels of these molecules in different brain regions of Rett mice. The 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 memory regulation – while miR-203 was upregulated in the cerebral cortex, which is involved in higher-level cognition. The other two messengers 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.

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In other tests, the researchers engineered neurons to express higher-than-normal levels of miR-101a or miR-203, and then assessed the cells’ electrical activity.

The results showed that increasing miR-101a levels enhanced the overall strength of excitatory transmissions – signals that prompt neurons to “fire” – while simultaneously reducing inhibitory signals that prevent cells from firing. By contrast, overexpression of miR-203 does not affect the electrical activity.

“Because miR-101a [overexpression] It resulted in opposite effects on spontaneous excitatory and inhibitory neurotransmission, and miR-101a is upregulated in MeCP2. [knockout] hippocampus, we concluded that miR-101a may be a major effector downstream of MeCP2 in the hippocampus,” the researchers wrote.

More detailed analyzes showed that overexpression of miR-101a increased the release of inhibitory signals from neurons, 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 at which individual signals were transmitted.

“Importantly, miR-101a affected synaptic phenotypes [characteristics] In both exciting and inhibiting clamps in contrasting ways. The authors conclude that these findings suggest that a single miRNA dysregulated in MeCP2 loss-of-function states could be responsible for extensive synaptic dysfunction in a specific brain region.

The team hypothesized that altered inhibitory and excitatory signals could lead to differences in brain circuits that ultimately lead to behavioral differences and other symptoms of Rett, although they stressed the need for further research into the specific abnormalities linking small RNA molecules to symptoms.

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