Reduction of microRNA targeting Drd2 leads to thalamocortical dysfunction in schizophrenia mouse models
  • Ph.D Sungkun Chun
  • SLS Colloquia / March 7th 04:00 pm / Bldg. 110 Room N104
Abstract

A specific disruption of synaptic transmission at thalamocortical (TC) glutamatergic projections in the auditory cortex is caused by an aberrant elevation of Drd2 in the auditory thalamus. This disruption renders 22q11DS TC projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenia patients. Through these findings, auditory TC projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS. Haploinsufficiency of the microRNA (miRNA)-processing-factor gene Dgcr8 is responsible for the elevation of the dopamine receptor Drd2 in the auditory thalamus (MGv) and hypersensitivity of auditory TC projections to antipsychotics. It also causes an abnormal acoustic-startle response.

Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

Keywords:  microRNA, Drd2, Thalamocortical dysfunction, 22q11DS, Schizophrenia