The role of GABA-mimetic metabolites in neurodevelopmental and neuropsychiatric d

GABA 模拟代谢物在神经发育和神经精神疾病中的作用

• 批准号: 8492293
• 负责人: JOSEPH A GOGOS
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-11 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492293
• 关键词: 22q11.2; Acute Intermittent Porphyria; Affect; Aminolevulinic Acid; Biochemical; Biological Assay; Brain; Chemical Structure; Chemicals; Chromosome Mapping; Databases; Detection; Development; Diagnostic; Disease; Electrophysiology (science); Epilepsy; Foundations; Frequencies; Functional disorder; Future; GABA transporter; GABA-A Receptor; GABA-B Receptor; Genes; Human; Individual; Ion Channel; Link; Lysine Degradation Pathway; Medial; Modeling; Mus; Mutant Strains Mice; Neuronal Dysfunction; Neurons; Neurotransmitters; Patients; Phenotype; Physiology; Pipecolic Acids; Play; Prefrontal Cortex; Process; Proline; Property; Psychotic Disorders; Research Design; Risk; Role; Schizoaffective Disorders; Schizophrenia; Seizures; Series; Severities; Slice; Structure; Synapses; Synaptic Transmission; Syndrome; System; Testing; Vitamin B6; analog; base; clinically relevant; drug development; enzyme activity; gamma-Aminobutyric Acid; heme biosynthesis; high risk; human disease; in vivo; information processing; insight; interest; loss of function mutation; meetings; microdeletion; mimetics; neuropsychiatry; novel; public health relevance; receptor function; research study; small molecule; synaptic function

DESCRIPTION (provided by applicant): Hyperprolinemia has been shown to correlate with the risk of psychosis, schizophrenia, schizoaffective disorder, and seizures in a number of human diseases. One cause of hyperprolinemia is loss-of-function mutations of the PRODH gene, which is involved in L-proline degradation. The PRODH gene maps in the 22q11.2 locus, and is heterozygously deleted in the 22q11.2 microdeletion syndrome, which is associated with high-risk for neurodevelopmental abnormalities and psychosis. One hypothesis explaining the effects of elevated L-proline within the CNS is that L-proline may act as a neuroactive small molecule that interferes with the normal function of other neurotransmitter systems within the brain. In preliminary studies we have found that L-proline is a GABA-mimetic metabolite capable of activating GABA-A receptor ion channels. Based on chemical structural database searches we have identified two additional "proline-like" metabolites that are known to accumulate in two other human neuropsychiatric diseases: -aminolevulinic acid, which accumulates in acute intermittent porphyria, a disease associated with psychosis and seizures, and L-pipecolic acid, which accumulates in pyridoxine (vitamin B6) dependent epilepsy, a disease associated with seizures. Similar to L-proline, we have found that both of these metabolites are also GABA-mimetic and capable of activating GABA-A receptors. We hypothesize that accumulation of these GABA-mimetic metabolites within the CNS may disrupt normal GABA-ergic synaptic transmission in these diseases with overlapping neuropsychiatric symptomatology. To test this hypothesis we have proposed the following Specific Aims: (1) to determine whether these metabolites interfere with normal GABA processing, handling, and detection by the components of the GABA-system and (2) to determine the impact of L-proline accumulation upon GABA-ergic synaptic transmission and network properties within the medial prefrontal cortex. The results of our proposed studies will provide important initial insights into the role of accumulated metabolites in GABA-ergic dysfunction in these clinically relevant human diseases with overlapping neurodevelopmental and neuropsychiatric dysfunction. These results will also lay the foundation for guiding future studies targeted at the development of pharmacological rescue strategies for these diseases.

描述（由申请人提供）：高脯氨酸血症已被证明与多种人类疾病中的精神病、精神分裂症、分裂情感性障碍和癫痫发作的风险相关。高脯氨酸血症的原因之一是 PRODH 基因的功能丧失突变，该基因参与 L-脯氨酸降解。 PRODH 基因定位于 22q11.2 基因座，并在 22q11.2 微缺失综合征中杂合缺失，该综合征与神经发育异常和精神病的高风险相关。解释中枢神经系统内 L-脯氨酸升高的影响的一个假设是，L-脯氨酸可能作为一种神经活性小分子，干扰大脑内其他神经递质系统的正常功能。 在初步研究中，我们发现L-脯氨酸是一种GABA模拟代谢物，能够激活GABA-A受体离子通道。根据化学结构数据库搜索，我们发现了另外两种“脯氨酸样”代谢物，已知它们在另外两种人类神经精神疾病中积累：-氨基乙酰丙酸，在急性间歇性卟啉症（一种与精神病和癫痫发作相关的疾病）中积累；L-哌啶酸，在吡哆醇（维生素 B6）依赖性癫痫（一种疾病）中积累。 与癫痫发作有关。与 L-脯氨酸类似，我们发现这两种代谢物也是 GABA 模拟物，并且能够激活 GABA-A 受体。 我们假设这些 GABA 模拟代谢物在中枢神经系统内的积累可能会破坏这些具有重叠神经精神症状的疾病中正常的 GABA 能突触传递。为了检验这一假设，我们提出了以下具体目标：(1) 确定这些代谢物是否干扰 GABA 系统组件的正常 GABA 加工、处理和检测；(2) 确定 L-脯氨酸积累对内侧前额叶皮层内 GABA 能突触传递和网络特性的影响。我们提出的研究结果将为以下方面提供重要的初步见解 在这些具有重叠的神经发育和神经精神功能障碍的临床相关人类疾病中，积累的代谢物在 GABA 能功能障碍中的作用。这些结果也将为指导未来针对这些疾病制定药物救援策略的研究奠定基础。