Role of Psychiatric Disease-associated Circular RNAs in Neuronal Function and Cognition

精神疾病相关环状 RNA 在神经元功能和认知中的作用

• 批准号: 9883048
• 负责人: Nikolaos Mellios
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883048
• 关键词: Autopsy; Back; Behavior; Behavioral; Bipolar Disorder; Brain; Categories; Cells; Code; Cognition; Cognitive; Data; Dendrites; Down-Regulation; Electrophysiology (science); Exons; Gene Expression; Gene Mutation; Genes; Glutamates; Goals; Homer protein; Homologous Protein; Human; Impairment; In Situ Hybridization; Introns; Joining Exons; Link; Medial; Mediating; Mental disorders; Messenger RNA; Molecular; Mus; Nature; Neurons; Pathogenesis; Patients; Prefrontal Cortex; Protein Isoforms; Proteins; Quantitative Reverse Transcriptase PCR; RNA Splicing; Research; Role; Schizophrenia; Startle Reaction; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Translating; Untranslated RNA; Work; behavior test; brain cell; circular RNA; cohort; design; differential expression; excitatory neuron; flexibility; genetic association; in vivo; induced pluripotent stem cell; insight; intein; knock-down; neuronal excitability; neuropsychiatric disorder; novel; socioeconomics; stem cells; synaptic function; touchscreen

PROJECT SUMMARY Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders with severe socioeconomic impacts and unknown pathogenesis. Circular RNAs (circRNAs) are a novel category of non- coding RNAs that are derived from the back-splicing and covalent joining of exons and introns of protein- coding genes, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are relatively enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neuropsychiatric disease. Here we carried out systematic profiling of circRNA expression in a large cohort of human postmortem brains from subjects with SCZ and BD and uncovered a subset of differentially expressed circRNAs produced from genes with known links to synaptic plasticity and neuronal excitability. We propose to study the function of the evolutionary conserved, neuronal-enriched circRNA, circHomer1, which is reduced in both the prefrontal cortex (PFC) of both BD and SCZ postmortem brains and in patient-derived neuronal cultures. We hypothesize that circHomer1 inhibits glutamatergic synaptic transmission and neuronal excitiability via inhibiting the expression and synaptic localization of plasticity-related Homer protein homolog 1 long isoform B (HOMER1B) mRNA, thereby disrupting PFC functions. We intend to knockdown circHomer1 expression in both induced pluripotent stem cell (iPSC)-derived neuronal cultures and mouse PFC and examine its role in neuronal fuction and psychiatric disease-related behavior. We will test our hypothesis via three specific aims: 1) Test the hypothesis that circHomer1 and HOMER1B mRNA levels are differentially altered in a cell-specific manner in human PFC and iPSC-derived neuronal cultures from patients with psychiatric disease. 2) Test the hypothesis that circHomer1 regulates synaptic efficacy and neuronal excitability through inhibition of HOMER1B localization. 3) Test the hypothesis that circHomer1 deficits in the PFC influence neuronal firing, cognitive flexibility, and sensorimotor gating.

项目总结

项目成果

Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder.

• DOI: 10.1038/s41398-021-01746-4
• 发表时间: 2021-12-10
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Lin R;Lopez JP;Cruceanu C;Pierotti C;Fiori LM;Squassina A;Chillotti C;Dieterich C;Mellios N;Turecki G
• 通讯作者: Turecki G