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）影响世界人口的1%左右，其特征是症状 包括幻觉和妄想（阳性症状）;反社会行为和迟钝的情绪 （阴性症状）;以及工作记忆、执行功能、学习和记忆（认知）缺陷 症状）。抗精神病药主要通过多巴胺受体（Drd 2）起作用，减轻阳性症状， 一些阴性症状，大多对认知症状无效。因此，多个神经回路和 机制涉及SCZ症状类别。由于SCZ的病因不明， 小鼠模型不可用，我们将重点放在22q11.2缺失综合征（22 q11 DS），最常见的 微缺失综合征，使SCZ的风险增加30倍。精神病症状在临床上 在伴或不伴22 q11 DS的SCZ患者中难以区分，通常出现在青春期晚期/早期 成年已构建并验证了22 q11 DS小鼠模型（22 q11 DS小鼠）。利用这些老鼠， 我们和其他人已经确定了一些认知和消极的细胞和分子机制， 22 q11 DS的症状在上一个资助期间，我们还发现了突触传递中断 在22 q11 DS小鼠听丘脑和听皮层（ACx）之间的丘脑皮层（TC）投射中， 人类大脑中这些区域的异常活动与幻听有关。TC中断 预测发生在小鼠3.5个月，这对应于人类青春期后期/成年早期， 阳性症状发作的年龄，并通过抗精神病药和Drd 2s的特异性抑制剂进行挽救。我们的研究 揭示了TC赤字是由丘脑传入神经的谷氨酸释放减少引起的，这是由于 22 q11 DS基因Dgcr 8的单倍不足，其介导microRNA（miR）生物合成。Dgcr8 单倍不足导致miR-338- 3 p耗尽，这反过来又提高了丘脑中继神经元中的Drd 2水平。 升高的Drd 2减少丘脑神经元中的谷氨酸释放。miR-338- 3 p的表达富集于 随着年龄的增长，丘脑和下降，这可能是丘脑特异性和迟发性发病机制的基础 TC中断。虽然TC机制似乎满足介导阳性症状的要求， 它如何影响ACx和听觉丘脑的网络活动尚不清楚。在这次竞争性续约申请中， 我们建议分析ACx和听丘脑神经元集合的异常自发活动 行为正常的老鼠。对于ACx，我们将通过颅窗使用双光子成像，对于听觉， 丘脑，我们将通过分级指数使用头戴式微型镜（单光子成像）或双光子成像 眼镜.我们还将研究miR-338- 3 p表达的年龄依赖性下降的机制。 并将其与22 q11 DS模型中ACx的迟发性异常同步性联系起来。这项工作将阐明 SCZ最神秘的症状的新机制，并提供了一个框架的发展， 具体的治疗干预，以减轻这种灾难性疾病患者的阳性症状。