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: 10382250
• 负责人: Stanislav S Zakharenko
• 金额: $ 47.01万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382250
• 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; Psychoses; 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; knock-down; lens; microdeletion; mouse model; neural circuit; neuromechanism; neuronal patterning; psychotic symptoms; relating to nervous system; schizophrenia risk; 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）影响约1%的世界人口，其特征是症状

项目成果

MicroRNA 3' ends shorten during adolescent brain maturation.

• DOI: 10.3389/fnmol.2023.1168695
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Thomas, Kristen T.;Vermare, Anais;Egleston, Suzannah O.;Wang, Yong-Dong;Mishra, Ashutosh;Lin, Tong;Peng, Junmin;Zakharenko, Stanislav S.
• 通讯作者: Zakharenko, Stanislav S.