title: Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models.
abstract: Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (Drd2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-Drd2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sungkun
authors.initials: S
authors.lastname: Chun
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Joby J
authors.initials: JJ
authors.lastname: Westmoreland
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ildar T
authors.initials: IT
authors.lastname: Bayazitov
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Donnie
authors.initials: D
authors.lastname: Eddins
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amar K
authors.initials: AK
authors.lastname: Pani
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Smeyne
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Blundon
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. stanislav.zakharenko@stjude.org.
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Zakharenko
mesh_terms: D058165:22q11 Deletion Syndrome / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001303:Auditory Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D057895:Haploinsufficiency; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis* / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics; D013788:Thalamus / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D017448:Receptors, Dopamine D2