miR-338-3p controls the late onset of auditory thalamocortical disruption in schizophrenia models. Mus musculus

Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset. Overall design: Profile the miRNA expression changes between wild type and mutant (Df(16)1/+, Dgcr8+/-) mice.