Chun Sungkun, Westmoreland Joby J, Bayazitov Ildar T, Eddins Donnie, Pani Amar K, Smeyne Richard J, Yu Jing, Blundon Jay A, Zakharenko Stanislav S
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Science. 2014 Jun 6;344(6188):1178-82. doi: 10.1126/science.1253895.
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.
精神分裂症中的幻听可通过抑制D2多巴胺受体（Drd2s）的抗精神病药物得到缓解。其神经回路缺陷及其对抗精神病药物敏感性的机制尚不清楚。我们在精神分裂症相关22q11缺失综合征（22q11DS）的小鼠模型中，发现听觉皮层丘脑皮质谷氨酸能投射处的突触传递存在特异性破坏。这种缺陷是由丘脑中Drd2异常升高引起的，这使得22q11DS丘脑皮质投射对抗精神病药物敏感，并导致类似于精神分裂症患者中观察到的听觉惊吓反应缺陷。微小RNA加工基因Dgcr8的单倍剂量不足是Drd2升高以及听觉丘脑皮质投射对抗精神病药物超敏反应的原因。这表明Dgcr8-微小RNA-Drd2依赖性丘脑皮质破坏是精神分裂症相关精神病的致病事件。
