Targeted Manipulation of KYNA in Mice by Genetic and Pharmacological Means: Biochemical and Functional Effects

通过遗传和药理学手段对小鼠 KYNA 进行靶向操作：生化和功能效应

• 批准号: 10425361
• 负责人: ROBERT SCHWARCZ
• 金额: $ 46.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425361
• 关键词: Acids; Acute; Address; Adolescence; Adult; Adult Children; Animals; Antipsychotic Agents; Astrocytes; Attention; Attenuated; Autopsy; Behavior; Behavioral; Biochemical; Biochemistry; Brain; Brain region; Cerebrospinal Fluid; Cognitive; Cognitive deficits; Data; Development; Dimensions; Disease; Electrophysiology (science); Embryo; Embryonic Development; Enzymes; Etiology; Event; Exhibits; Exposure to; Functional disorder; Genes; Genetic; Genetic Polymorphism; Glutamates; Hippocampus (Brain); Impaired cognition; Individual; Intervention; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Kynurenine-oxoglutarate aminotransferase; Lead; Mediating; Memory; Messenger RNA; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Nicotinic Receptors; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Play; Prefrontal Cortex; Pregnancy; Psychopathology; Rattus; Regulation; Risk; Risk Factors; Rodent; Role; Schizophrenia; Testing; Therapeutic; Tissues; Tryptophan; antagonist; base; behavioral impairment; behavioral outcome; brain tissue; choline supplementation; cognitive function; combat; design; executive function; experimental study; extracellular; fetal; inhibitor; insight; postnatal; prenatal; prenatal exposure; receptor; transmission process; treatment strategy

Project Summary Pathological events during early brain development are believed to hold the key to the emergence of schizophrenia (SZ) in adulthood. Deficits in memory, attention and executive function, i.e. core domains of the psychopathology of SZ, might be causally related to dysfunctional glutamatergic and nicotinergic transmission. Kynurenine acid (KYNA), an astrocytic metabolite of the kynurenine pathway of tryptophan degradation, is an endogenous inhibitor of ±7nACh and NMDA receptors in the brain and has been implicated in the pathology of SZ. Studies using cerebrospinal fluid (CSF) or post-mortem brain tissue of patients with SZ suggest that an excess of KYNA might play a causative role in the disease. As an endogenous antagonist at ±7nAChRs and NMDARs, which are both critically involved in cognitive functions, increased KYNA levels in the brain might be especially involved in the cognitive deficits that are seen in individuals with SZ. Importantly, a polymorphism in the gene for kynurenine 3-monooxygenase (KMO), an enzyme involved in the regulation of KYNA neosynthesis, has been associated with elevated KYNA levels and increased risk of developing SZ. The connection between KYNA and SZ may have a developmental dimension as several of the risk factors associated with SZ result in increased formation of kynurenine, the direct bioprecursor of KYNA. The proposed project is based on recent studies showing that elevating brain KYNA in the last week of gestation impaires cognitive functions in the adult offspring. In this context, we propose to build on the model by using genetically modified mice, heterozygous for the Kmo gene, and increasing brain KYNA during the last week of embryonic development. Making comparisons to wild-type controls, we will examine the impact of prolonged exposure to kynurenine in a vulnerable animal that has reduced KMO enzymatic activity. The central hypothesis of this proposal is that elevated KYNA during the prenatal development, produced from its bioprecursor kynurenine, influences the development of the brain and, as a result, alters KP dynamics, extracellular glutamate, modulates hippocampal-mediated cognitive behaviors, and interhemispheric transmission in adulthood. It follows, and will be tested here, that inhibition of KYNA synthesis is a valuable therapeutic strategy to combat cognitive deficits in SZ.

项目概要 早期大脑发育过程中的病理事件被认为是出现的关键 成年期精神分裂症（SZ）的记忆、注意力和执行功能（即大脑的核心领域）缺陷。 SZ 的精神病理学可能与谷氨酸能和烟碱能传递功能失调有关。 犬尿氨酸 (KYNA) 是色氨酸降解犬尿氨酸途径的星形胶质细胞代谢产物，是一种 大脑中 ±7nACh 和 NMDA 受体的内源性抑制剂，与以下疾病的病理学有关 SZ。使用 SZ 患者的脑脊液 (CSF) 或死后脑组织进行的研究表明， 过量的 KYNA 可能作为 ±7nAChR 的内源性拮抗剂在该疾病中发挥致病作用。 NMDAR 都与认知功能密切相关，大脑中 KYNA 水平的增加可能与 尤其与精神分裂症患者的认知缺陷有关。重要的是，它存在多态性。 犬尿氨酸 3-单加氧酶 (KMO) 基因，一种参与 KYNA 调节的酶 新合成与 KYNA 水平升高和发生 SZ 的风险增加有关。 KYNA 和 SZ 之间的联系可能具有发展维度，因为有几个风险因素 与 SZ 相关导致犬尿氨酸（KYNA 的直接生物前体）形成增加。 拟议的项目基于最近的研究，表明在妊娠最后一周升高大脑 KYNA 损害成年后代的认知功能。在这种情况下，我们建议使用该模型来构建。 转基因小鼠，Kmo 基因杂合，并在最后一周增加大脑 KYNA 与野生型对照进行比较，我们将检查长期的影响。 脆弱动物接触犬尿氨酸会降低 KMO 酶活性。 该提议的假设是，在产前发育期间，KYNA 升高，由其产生 生物前体犬尿氨酸，影响大脑的发育，从而改变 KP 动力学， 细胞外谷氨酸，调节海马介导的认知行为和半球间 由此可见，抑制 KYNA 合成是有价值的，并将在此进行测试。 对抗 SZ 认知缺陷的治疗策略。