Small sections of non-coding RNA could provide the clue to schizophrenia's "voices."
Although much study has gone into schizophrenia, its causes, and its potential treatments, there are many unanswered questions.
Characterized by deficits in a range of mental processes, one of the most distressing symptoms can be hallucinations.
These can affect any of the senses, but auditory hallucinations are most common.
Research, published this week in Nature Medicine, investigated the origins of auditory hallucinations using a mouse model that replicates a genetic predisposition for schizophrenia.
The study built on previous investigations at St. Jude, in which they examined the molecular mechanisms that disrupt the flow of information within neural circuits that connect brain centers involved in processing auditory information.
Mouse model of auditory hallucinations
The mouse model that the researchers used mimics 22q11 deletion syndrome, also known as DiGeorge syndrome. This condition is due to a fault in a specific chromosome. Individuals with 22q11 deletion syndrome are more likely to develop psychiatric conditions; an estimated 23-43 percent go on to develop schizophrenia.
The research team identified small RNA sequences, or microRNAs, that could potentially be targeted for the creation of a new range of antipsychotic drugs with reduced side effects.
MicroRNAs are noncoding RNA molecules, meaning that they are not responsible for coding specific proteins. There are more than 2,000 MicroRNAs, and they are generally involved in regulating and silencing gene expression.
"In 2014, we identified the specific circuit in the brain that is targeted by antipsychotic drugs. However, the existing antipsychotics also cause devastating side effects. In this study, we identified the microRNA that is a key player in disruption of that circuit and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse model."
Corresponding author Dr. Stanislav Zakharenko, Ph.D.
The specific microRNA that caught the researchers' eye is miR-338-3p. This microRNA regulates the manufacture of protein D2 dopamine receptor (Drd2) - a primary target of antipsychotics. Zakharenko and his team found that as microRNA levels declined, levels of Drd2 increased in the auditory thalamus - a brain region associated with auditory hallucinations.
Dr. Zakharenko's earlier work showed that increased Drd2 in the auditory thalamus is linked to brain-circuit disruptions in the mouse model. Other studies have also found that Drd2 levels are elevated in this brain region in humans with schizophrenia, compared with those without the disorder.
How does 22q11 deletion syndrome impact Drd2?
Individuals with 22q11 deletion syndrome are missing parts of chromosome 22. In all, 25 genes are missing their second copy. These missing genes include Dgcr8, a portion which is important for the production of microRNAs.
Previous investigations by the team found a relationship between the deletion of Dgcr8 and age-related declines in miR-338-3p in the auditory thalamus.
This reduction was linked to an increase in Drd2 and a reduction in activity within the circuit that links the auditory cortex and thalamus. In the thalamus of individuals with schizophrenia, levels of miR-338-3p were lower compared with individuals of the same gender and age without the condition.
Replenishing microRNA in the auditory thalamus of the mice decreased Drd2 protein levels, and the circuit returned to normal functioning.
This finding hints that microRNAs could form the basis of new antipsychotics. It is hoped that these results might lead to more effective interventions with limited side effects.