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) 影响着世界上约 1% 的人口，其特点是症状 包括幻觉和妄想（阳性症状）； （阴性症状）；以及工作记忆、执行功能以及学习和记忆（认知）缺陷 抗精神病药主要通过多巴胺受体（Drd2s）积极缓解症状， 一些阴性症状，并且对认知症状大多无效，因此，多个神经回路和 SCZ 症状类别涉及机制，因为 SCZ 的病因尚不清楚，且 SCZ 有效。 没有小鼠模型，我们关注最常见的 22q11.2 缺失综合征 (22q11DS) 人类微缺失综合征，临床上出现 SCZ 的风险增加 30 倍。 在有或没有 22q11DS 的 SCZ 患者中难以区分，通常出现在青春期晚期/早期 使用这些小鼠构建并验证了 22q11DS 的成年小鼠模型。 我们和其他人已经确定了某些负面影响背后的细胞和分子机制 在之前的资助期间，我们还发现了 22q11DS 的突触传递中断的症状。 22q11DS 小鼠听觉丘脑和听觉皮层 (ACx) 之间的丘脑皮质 (TC) 投射。 人类这些大脑区域的异常活动与幻听有关。 小鼠的预测发生在 3.5 个月大时，这对应于人类的青春期晚期/成年早期， 阳性症状出现的年龄，并且可以通过抗精神病药物和 Drd2s 的特异性抑制剂来挽救。 揭示 TC 缺乏是由于丘脑传入神经释放谷氨酸减少造成的，这是由于 22q11DS 基因 Dgcr8 的单倍体不足，该基因介导 microRNA (miR) Dgcr8 的生物合成。 单倍体不足会导致 miR-338-3p 耗竭，进而升高丘脑中继神经元中的 Drd2 水平。 Drd2s 升高会减少丘脑神经元中谷氨酸的释放。miR-338-3p 的表达丰富。 丘脑并随着年龄的增长而衰退，这可能是丘脑特异性和晚发机制的基础 尽管 TC 机制似乎满足调解阳性症状的要求， 它如何影响 ACx 和听觉丘脑的网络活动尚不清楚。 我们建议分析 ACx 和听觉丘脑神经群的异常自发活动 对于行为小鼠，我们将使用通过颅窗的 2 光子成像，对于听觉。 丘脑，我们将使用头戴式微型显微镜（1 光子成像）或通过分级索引进行 2 光子成像 我们还将研究 miR-338-3p 表达随年龄下降的机制。 并将其与 22q11DS 模型 ACx 的晚期异常同步性联系起来。这项工作将阐明。 SCZ 最神秘症状的新机制，并为开发提供框架 减轻这种灾难性疾病患者的阳性症状的具体治疗干预措施。