Publication Date:
2014-06-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349506/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349506/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chun, Sungkun -- Westmoreland, Joby J -- Bayazitov, Ildar T -- Eddins, Donnie -- Pani, Amar K -- Smeyne, Richard J -- Yu, Jing -- Blundon, Jay A -- Zakharenko, Stanislav S -- R01 DC012833/DC/NIDCD NIH HHS/ -- R01 MH095810/MH/NIMH NIH HHS/ -- R01 MH097742/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1178-82. doi: 10.1126/science.1253895.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. stanislav.zakharenko@stjude.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904170" target="_blank"〉PubMed〈/a〉
Keywords:
22q11 Deletion Syndrome/drug therapy/*genetics
;
Animals
;
Antipsychotic Agents/therapeutic use
;
Auditory Cortex/*metabolism
;
Disease Models, Animal
;
Drug Resistance/genetics
;
*Haploinsufficiency
;
Mice
;
Mice, Mutant Strains
;
MicroRNAs/metabolism
;
RNA-Binding Proteins/*genetics
;
Receptors, Dopamine D2/*biosynthesis/genetics
;
Schizophrenia/drug therapy/*genetics
;
Synaptic Transmission/genetics
;
Thalamus/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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