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At Least One MicroRNA Mediates Brain's Alcohol Tolerance

NEW YORK (GenomeWeb News) – A brain-specific microRNA has a key role in the development of some forms of alcohol tolerance, new research suggests.
In a paper appearing online this week in Neuron, researchers from the University of Massachusetts identified a miRNA — called miR-9 — that is up-regulated in rat brain cells in the presence of alcohol. The miRNA seems to exert post-transcriptional control over the stability of certain alcohol tolerance-related splice variants. That, in turn, can alter the way neurons react to alcohol, boosting their tolerance.
“This represents a novel and elegant mechanism by which neurons are able to adapt to alcohol,” senior author Steven Treistman, a neurobiologist and director of the University of Massachusetts’ Brudnick Neuropsychiatric Research Institute, said in a statement. “Moreover, since adaptation, or tolerance, to the drug likely contributes to alcohol abuse, our findings identify a potential molecular target for therapeutic intervention.”
Regular exposure to alcohol can decrease an individual’s alcohol sensitivity, increasing the likelihood that he or she will become dependent on the substance. Previous research has shown that such tolerance involves BK channels, large-conductance calcium and voltage-activated potassium channels that regulate neuronal excitability. Over time, the density of these channels decreases in regions of the brain called the supraoptic nucleus, or SON, and the striatum as alcohol tolerance increases.
In an effort to understand the molecular basis of this alcohol tolerance, Treistman and his colleagues looked at the BK mRNA variants present in the SON and striatum of rat brain cells that were unexposed or exposed to alcohol. They found several BK splice variants — the identity of which shifted in the presence of alcohol, apparently post-transcriptional mechanisms.
That observation fueled speculation that one or more miRNAs was involved. To determine which miRNAs, if any, regulate BK mRNA, the team looked for BK mRNA-interacting miRNAs by base-pairing more than 100 rodent neuronal miRNAs with the 3’ untranslated region of rat BK mRNA.
The search turned up miR-9, a brain-specific miRNA involved in neurogenesis. Subsequent experiments showed that miR-9 levels increase in response to alcohol, concurrent with alterations in BK mRNA community composition. This alcohol-dependent post-transcriptional BK mRNA regulation appears to cull the most alcohol-sensitive BK splice variants, leaving behind more tolerant variants. 
But miR-9’s influence did not seem to stop at the BK mRNA. The miRNA also seems to mediate at least ten other alcohol-related mRNA targets in the brain. These mRNAs, most of which are down-regulated by miR-9, appear to be involved in processes such as neuronal excitability, gene expression, lipid metabolism, and pre-synaptic function.
“[A]lcohol, via miR-9 upregulation, regulates additional targets, suggesting a central role for miR-9 in alcohol’s actions in the CNS,” the authors wrote.
Even so, miR-9 doesn’t explain all BK channel-related alcohol tolerance. Some BK channel tolerance is governed by miR-9, but there are also situations in which tolerance occurs in the absence of miR-9. Similarly, there are different forms of alcohol tolerance, ranging from acute to chronic, that may depend on the action of other miRNAs. Still, the work provides new insights into alcohol tolerance that may eventually benefit those with alcohol dependence.
“The study demonstrates for the first time that alcohol exposure can cause rapid changes in miRNA levels, altering gene expression and perhaps behavior,” Antonio Noronha, director of the National Institute of Alcohol Abuse and Alcoholism’s Division of Neuroscience and Behavior, said in a statement. “In future studies, it will be interesting to determine if similar miRNA-based regulatory mechanisms influence alcohol problems in human populations.”

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