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

描述(由申请人提供)：在许多人类疾病中，高脯氨酸血症已被证明与精神病、精神分裂症、分裂情感障碍和癫痫的风险相关。高脯氨酸血症的一个原因是PROSH基因的功能缺失突变，该基因与L-脯氨酸的降解有关。该基因定位于22q11.2位点，在22q11.2微缺失综合征中杂合性缺失，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-脯氨酸升高效应的一个假说是，L-脯氨酸可能是一种神经活性小分子，干扰了大脑内其他神经递质系统的正常功能。我们在初步研究中发现，L-脯氨酸是一种能激活GABA-A受体离子通道的类似于GABA的代谢产物。基于化学结构数据库的搜索，我们已经确定了另外两种已知在另外两种人类神经精神疾病中积累的“类脯氨酸”代谢物：-氨基酮丙酸，它在急性间歇性卟啉症中积累，这是一种与精神病和癫痫有关的疾病；以及L-吡哌酸，它在吡哆醇(维生素B6)依赖型癫痫中积累，这是一种与癫痫相关的疾病。与L-脯氨酸类似，我们发现这两种代谢物也都是GABA类似物，并能够激活GABA-A受体。我们推测，这些类似GABA的代谢物在中枢神经系统内的积累可能会扰乱这些具有重叠神经精神症状的疾病的正常GABA能突触传递。为了验证这一假说，我们提出了以下具体目标：(1)确定这些代谢物是否干扰GABA系统的正常处理、处理和检测；(2)确定L-Pro积聚对内侧前额叶皮质GABA能突触传递和网络特性的影响。我们建议的研究结果将为以下方面提供重要的初步见解 在这些临床相关的人类疾病中，累积代谢产物在GABA能功能障碍中的作用，这些疾病有重叠的神经发育和神经精神功能障碍。这些结果还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。

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.