Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion

Abstract

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and 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.

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Figure 1: Adult onset of sensitivity to antipsychotics and of synaptic transmission disruption in auditory TC projections in mouse models of 22q11DS.
Figure 2: Identification of Drd2-targeting miR-338-3p in the auditory thalamus.
Figure 3: Replenishment of miR-338-3p in the auditory thalamus rescues deficits in synaptic transmission and presynaptic neurotransmitter release at TC projections in 22q11DS mouse models.
Figure 4: The depletion of mir-338-3p or knockout of Mir338 replicates the TC deficiency of Df(16)1/+ mice.
Figure 5: Probability of glutamate release is reduced at TC projections from Mir338+/− mice.
Figure 6: Deletion of Mir338 in mice eliminates age dependency for sensitivity to antipsychotics and replicates 22q11DS phenotypes.

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Acknowledgements

This work was supported by the National Institutes of Health grants MH097742 (S.S.Z.), DC012833 (S.S.Z.), and MH095810 (S.S.Z.), the NARSAD Independent Investigator Award (S.S.Z.), and ALSAC (S.S.Z.). The funding sources had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript. We thank the St. Jude Vector Core for producing the AAVs, the St. Jude Hartwell Center for Biotechnology and Bioinformatics for performing the microarrays, the Maryland Brain Collection for providing post-mortem human brain samples, and A. McArthur for editing the manuscript. Knockout mice, viruses and other materials described in this manuscript can be obtained through a material transfer agreement.

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S.S.Z., J.J.W., F.D., and S.C. designed the research; S.C. performed the whole-cell recordings; F.D., J.J.W., and S.B.H. designed and constructed the microRNA molecular tools and verified these tools in vitro and in vivo; Y.-D.W. performed the microRNA array analysis; I.T.B. and P.D. performed the two-photon imaging and whole-cell recordings; J.Y. and K.A. assisted with qRT–PCR and western blotting analyses; D.E. and M.M.M.L. performed the mouse behavior experiments; and S.S.Z. wrote the paper with help from the other authors.

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Correspondence to Stanislav S Zakharenko.

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Chun, S., Du, F., Westmoreland, J. et al. Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion. Nat Med 23, 39–48 (2017). https://doi.org/10.1038/nm.4240

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