Synaptic Protein Networks, Genetic Risk, and Spine Loss in Schizophrenia

精神分裂症的突触蛋白网络、遗传风险和脊柱缺失

• 批准号: 9816717
• 负责人: Matthew L MacDonald
• 金额: $ 50.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816717
• 关键词: AMPA Receptors; Acute; Adult; Antipsychotic Agents; Area; Auditory; Auditory Hallucination; Auditory area; Automobile Driving; Autopsy; Biological Assay; Brain; CRISPR/Cas technology; Code; Complex; Computer Analysis; Confocal Microscopy; Dendritic Spines; Dependovirus; Development; Disease model; Drug Targeting; Event; Future; Gene Proteins; Genes; Genetic; Genetic Risk; Genetic study; Genomics; Genotype; Glutamate Receptor; Glutamates; Immune; Impairment; Learning; Link; Maps; Mass Spectrum Analysis; Measures; Mental disorders; Methods; Microscopy; Modeling; Molecular; Monkeys; Mus; Neurobehavioral Manifestations; Neurons; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Post-Translational Protein Processing; Preparation; Process; Protein Analysis; Proteins; Proteomics; Pyramidal Cells; Regulation; Reporting; Role; Schizophrenia; Shotguns; Site; Slice; Synapses; Synaptosomes; TFAP2A gene; Testing; Vertebral column; causal model; cohort; density; disorder risk; drug discovery; experimental study; glutamatergic signaling; gray matter; imaging study; in vivo; in vivo two-photon imaging; innovation; instrumentation; link protein; mature animal; novel; novel therapeutics; paralemmin; postsynaptic; protein expression; protein transport; psychotic symptoms; recruit; risk variant; screening; social cognition; synaptogenesis; trafficking; two photon microscopy

Abstract Schizophrenia (Sz) is a lifelong and devastating psychiatric illness with limited treatment options and no cure. Layer 3 pyramidal cell dendritic spine loss has been repeatedly observed in multiple brain areas in schizophrenia (Sz), including the primary auditory cortex (AI). Spine loss is postulated to underlie primary auditory cortex processing deficits observed in Sz, contributing to impaired social cognition and auditory hallucinations in Sz. We have shown that only smaller spines are lost in Sz Al layer 3. Recent two-photon in vivo imaging studies have shown that new spines are small, essential for synaptogenesis, and required for new learning in adult animals. Dendritic spine formation, stabilization, and plasticity are regulated by synaptic protein network (SynPN) features, such as protein expression, trafficking, and phosphorylation (Phos), and a significant number of Sz risk loci code for synaptic proteins. Targeted and shotgun mass spectrometry (MS) approaches found robust changes in synaptosome and Phos levels of canonical postsynaptic proteins in Sz. These changes were not explained by corresponding changes in homogenate levels of these proteins, suggesting that the brunt of SynPN pathology in Sz is regulated by processes beyond protein expression (e.g. protein trafficking and activity). Nine Phos sites on eight proteins were highly correlated with both synaptosome protein levels and small spine density. All but one of these 8 proteins have well documented roles in vesicular trafficking of postsynaptic glutamate receptors and spine regulation. Postsynaptic glutamate signaling is one of the most significantly implicated pathways in genetic studies of Sz. Thus, we hypothesize that: Aberrant trafficking and Phos of postsynaptic proteins is linked to Sz genetic risk and drives small spine loss in Sz Al. We will test this hypothesis in an unprecedented set of parallel genomic, proteomic, and microscopy experiments in 100 Sz and 100 matched control subjects with cutting edge computational analyses to identify protein and Phos linked to Sz genetics and generate causal models of disease (Aim 1). We will then utilize innovative molecular and two-photon microscopy approaches to test the effects of candidate Phos, from our preliminary studies and high priority Aim 1 findings, on spine density, size, formation, and stability in the Al of adult mice (Aim 2). These studies will identify proximal molecular events, potentially associated with Sz risk genetics, that impair small spines in Sz Al, as well as the stage of spine formation/stabilization that is impaired. Such events can be further investigated in vivo via CRISPR/Cas9 in future studies and have the potential to serve as targets for the development of novel therapeutics.

摘要