Towards understanding cellular mechanisms of positive symptoms of schizophrenia

理解精神分裂症阳性症状的细胞机制

• 批准号: 9899300
• 负责人: Stanislav S Zakharenko
• 金额: $ 49.48万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899300
• 关键词: 22q11.2; Address; Adolescence; Affect; Age; Anabolism; Animals; Antipsychotic Agents; Attention; Auditory; Auditory Hallucination; Auditory area; Back; Biochemical; Biological Markers; Brain region; Calcium; Categories; Cephalic; Clinical; Clinical Research; Cognitive; Data; Delusions; Dependence; Development; DiGeorge Syndrome; Diagnosis; Disease; Dopamine Receptor; Emotions; Enzymes; Etiology; Evaluation; Event; Fire - disasters; Funding; Generations; Genes; Glutamates; Government; Hallucinations; Hallucinogens; Head; Human; Image; Individual; Interneurons; Learning; Life; Mediating; Memory; Metabolism; MicroRNAs; Microscope; Modality; Modeling; Molecular; Morphology; Mus; Neurobehavioral Manifestations; Neurons; Pathway interactions; Patients; Pattern; Persons; Phenotype; Photons; Population; Poverty; Psychotic Disorders; Risk; Saint Jude Children' s Research Hospital; Schizophrenia; Short-Term Memory; Specificity; Speech; Symptoms; Synaptic Transmission; Syndrome; Testing; Thalamic structure; Therapeutic Intervention; Up-Regulation; Wild Type Mouse; Work; age related; antisocial behavior; auditory thalamus; base; early adolescence; emerging adult; excitatory neuron; executive function; genetic predictors; genomic locus; human data; indexing; inhibitor/antagonist; knock-down; lens; microdeletion; mouse model; neural circuit; neuromechanism; neuronal patterning; psychotic symptoms; relating to nervous system; sensory cortex; sound; two-photon

Schizophrenia (SCZ) affects about 1% of the world’s population and is characterized by symptoms that include hallucinations and delusions (positive symptoms); antisocial behavior and blunted emotions (negative symptoms); and deficits in working memory, executive function, and learning and memory (cognitive symptoms). Antipsychotics primarily acting through dopamine receptors (Drd2s) alleviate positive symptoms, some negative symptoms, and are mostly ineffective for cognitive symptoms. Thus, multiple neural circuits and mechanisms are implicated in SCZ symptom categories. Because the etiology of SCZ is unknown and valid SCZ mouse models are not available, we focus on 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome in humans, which increases the risk of SCZ 30 fold. Psychotic symptoms are clinically indistinguishable in patients with SCZ with or without 22q11DS and usually appear during late adolescence/early adulthood. Mouse models of 22q11DS (22q11DS mice) have been constructed and validated. Using these mice, we and others have identified cellular and molecular mechanisms underlying some cognitive and negative symptoms of 22q11DS. During the previous funding period, we also identified disrupted synaptic transmission in thalamocortical (TC) projections between the auditory thalamus and auditory cortex (ACx) in 22q11DS mice. Abnormal activity in these brain regions in humans is associated with auditory hallucinations. Disruption of TC projections occurs in mice at 3.5 months, which corresponds to late adolescence/early adulthood in humans, the age of positive symptom onset, and is rescued by antipsychotics and specific inhibitors of Drd2s. Our studies revealed that the TC deficit is caused by reduced glutamate release from thalamic afferents, resulting from the haploinsufficiency of the 22q11DS gene Dgcr8, which mediates microRNA (miR) biosynthesis. Dgcr8 haploinsufficiency leads to depletion of miR-338-3p, which in turn, elevates Drd2 levels in thalamic relay neurons. Elevated Drd2s decrease glutamate release in thalamic neurons. The expression of miR-338-3p is enriched in the thalamus and declines with age, which may underlie thalamus specificity and the mechanism of late onset of TC disruption. Although the TC mechanism appears to satisfy requirements for mediating positive symptoms, how it affects network activity in the ACx and auditory thalamus is unclear. In this competitive renewal application, we propose to analyze abnormal spontaneous activity in neuronal ensembles in the ACx and auditory thalamus in behaving mice. For the ACx, we will use 2-photon imaging through a cranial window, and for the auditory thalamus, we will use a head-attached miniscope (1-photon imaging) or 2-photon imaging through graded index lenses. We will also study the mechanisms underlying age-dependent decline in the expression of miR-338-3p and connect it to the late onset of abnormal synchronicity in the ACx of 22q11DS models. This work will elucidate new mechanisms of the most enigmatic symptoms of SCZ and provide a framework for the development of specific therapeutic interventions to alleviate positive symptoms in patients with this catastrophic disease.

精神分裂症（SCZ）影响了世界人口的1％，其特征是符号 其中包括幻觉和妄想（正符号）；反社会行为和钝性情绪 （负面症状）；并在工作记忆，执行功能以及学习和记忆（认知）中定义 通过多巴胺受体（DRD2S）作用的抗精神病药原发性作用，减轻了积极症状， 一些负面症状，主要对认知症状无效。那是多个神经元电路 机制是在SCZ符号类别中实现的。因为SCZ的病因是未知且有效的SCZ 鼠标模型不可用，我们重点关注22Q11.2删除综合征（22q11ds），这是最常见的 人类中的微骨骼综合征，这增加了SCZ 30倍的风险。精神病症状在临床上 在患有或没有22Q11D的SCZ患者中无法区分，通常出现在青春期晚期/早期 成年。已经构建并验证了22q11ds（22q11ds小鼠）的鼠标模型。使用这些小鼠， 我们和其他人已经确定了某些认知和阴性的细胞和分子机制 22q11ds的症状。在上一个资金期间，我们还确定了破坏的突触传输 在22q11ds小鼠中的听觉丘脑和听觉皮层（ACX）之间的丘脑皮层（TC）项目中。 这些大脑区域的异常活动与听觉幻觉有关。 TC的破坏 在3.5个月的小鼠中进行预测，这对应于青少年晚期/成年早期的人类， 阳性症状发作的年龄，并以DRD2的抗精神病药和特定抑制剂做出反应。我们的研究 揭示了TC缺陷是由丘脑嗜热剂释放的减少引起的 22q11ds基因DGCR8的单倍不足，该基因介导microRNA（miR）生物合成。 DGCR8 单倍不足会导致miR-338-3p的耗竭，从而升高丘脑继电器神经元中的DRD2水平。 DRD2S升高可减少丘脑神经元中的谷氨酸释放。 miR-338-3p的表达富含 丘脑和随着年龄的增长而下降，这可能是丘脑特异性的基础和后期发病的机制 尽管TC机制似乎满足介导积极症状的要求，但 它如何影响ACX和听觉丘脑中的网络活动尚不清楚。在此竞争性更新应用中， 我们建议分析ACX和听觉丘脑中神经元合奏中的异常赞助商活性 在行为小鼠中。对于ACX，我们将通过颅骨窗口和听觉使用2光子成像 丘脑，我们将通过渐变索引使用式米斯科托（1光量成像）或2光子成像 镜片。我们还将研究miR-338-3p表达的年龄依赖性下降的机制 并将其连接到22Q11DS模型ACX中异常同步性的晚期发作。这项工作将阐明 SCZ最神秘符号的新机制，为开发的框架提供了一个框架 特定的治疗干预措施可减轻这种灾难性疾病患者的积极症状。