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: 8675291
• 负责人: JOSEPH A GOGOS
• 金额: $ 24万
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675291
• 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）：已证明高脯氨酸血症与许多人类疾病中的精神病、精神分裂症、情感性精神障碍和癫痫发作的风险相关。高脯氨酸血症的一个原因是PRODH基因的功能丧失突变，其参与L-脯氨酸降解。PRODH基因定位于22q11.2位点，并在22q11.2微缺失综合征中异源缺失，这与神经发育异常和精神病的高风险相关。解释CNS内升高的L-脯氨酸的作用的一种假设是，L-脯氨酸可能充当干扰脑内其他神经递质系统的正常功能的神经活性小分子。 在初步研究中，我们发现L-脯氨酸是一种能够激活GABA-A受体离子通道的GABA模拟代谢物。基于化学结构数据库搜索，我们已经确定了两个额外的“脯氨酸样”代谢物，已知积累在其他两个人类神经精神疾病：-氨基乙酰丙酸，积累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，和L-哌啶酸，积累在吡哆醇（维生素B6）依赖性癫痫，与癫痫发作相关的疾病。与L-脯氨酸类似，我们发现这两种代谢物也是GABA模拟物，能够激活GABA-A受体。 我们推测，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疾病与重叠的神经精神病学的正常GABA能突触传递。为了验证这一假设，我们提出了以下具体目标：（1）确定这些代谢物是否干扰正常GABA加工、处理和GABA系统组分的检测;（2）确定L-脯氨酸蓄积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提供重要的初步见解， 这些临床相关的人类疾病中GABA能功能障碍的累积代谢物的作用与重叠的神经发育和神经精神功能障碍。这些结果也将为指导未来的研究奠定基础，针对这些疾病的药物救援策略的发展。