The finding suggests that the microRNA could be a specific target for a new class of antipsychotic medications with fewer side effects.
In laboratory research using mice models, Stanislav Zakharenko, M.D., Ph.D., and colleagues at St. Jude Children’s Research Hospitals identified a microRNA (known as miR-338-3p) that regulates production of the protein D2 dopamine receptor (Drd2). In previous work, Zakharenko and colleagues linked elevated levels of Drd2 in the auditory thalamus to brain-circuit disruptions in the mutant mice. Additionally, the protein was elevated in the same brain region of individuals with schizophrenia, but not healthy adults.
In the Nature Medicine paper, the researchers reported that a decline in miR-338-3p and associated increase in Drd2 resulted in reduced signaling in the circuit that links the thalamus and auditory cortex, a brain region implicated in auditory hallucinations. Levels of miR-338-3p are also lower in the thalamus of individuals with schizophrenia compared with individuals of the same age and sex without the diagnosis.
Replenishing levels of the microRNA in the auditory thalamus of mutant mice reduced Drd2 protein and restored the circuit to normal functioning. That suggests that the microRNA could be the basis for a new class of antipsychotic medications that act in a more targeted manner with fewer side effects.
The researchers noted that levels of miR-338-3p appear to decline as normal mice age, but are liable to remain above the threshold necessary to prevent overexpression of the Drd2 protein (and the resulting disruption of the auditory circuit). In contrast, mice with the mutation appear to be at risk for dropping below that threshold.
“[W]e identified the microRNA that is a key player in disruption of that circuit [linking the thalamus and auditory cortex] and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse models,” Zakharenko said in a statement on the St. Jude’s website. “A minimum level of the microRNA may be necessary to prevent excessive production of the Drd2 that disrupts the circuit.”
For related information see the Psychiatric News article “Genomic Analysis Yields Link Between Gene Networks, Schizophrenia Types.”