title: 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.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Sungkun
authors.initials: S
authors.lastname: Chun
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Joby J
authors.initials: JJ
authors.lastname: Westmoreland
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Seung Baek
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yong-Dong
authors.identifier: 0000-0001-8751-9216
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Donnie
authors.initials: D
authors.lastname: Eddins
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ildar T
authors.initials: IT
authors.lastname: Bayazitov
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Devaraju
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Mellado Lagarde
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Stanislav S
authors.identifier: 0000-0001-8115-202X
authors.initials: SS
authors.lastname: Zakharenko
mesh_terms: D017668:Age of Onset; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001303:Auditory Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001306:Auditory Pathways / Q000187:drug effects / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009434:Neural Pathways; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011618:Psychotic Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D016601:RNA-Binding Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017448:Receptors, Dopamine D2 / Q000235:genetics; D013216:Reflex, Startle; D012559:Schizophrenia / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D014150:Antipsychotic Agents; C000600618:DRD2 protein, mouse; C474044:Dgcr8 protein, mouse; C532050:MIRN338 microRNA, human; D035683:MicroRNAs; C000591274:Mirn338 microRNA, mouse; D016601:RNA-Binding Proteins; D017448:Receptors, Dopamine D2