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、分裂情感性障碍和癫痫发作的风险相关。高脯氨酸血症的一个原因是与l -脯氨酸降解有关的PRODH基因的功能丧失突变。PRODH基因定位于22q11.2位点，在22q11.2微缺失综合征中被杂合缺失，这与神经发育异常和精神病的高风险相关。有一种假说解释了中枢神经系统中l -脯氨酸升高的影响，即l -脯氨酸可能作为一种神经活性小分子，干扰大脑中其他神经递质系统的正常功能。在初步研究中，我们发现l -脯氨酸是一种能够激活GABA-A受体离子通道的模拟gaba代谢物。基于化学结构数据库搜索，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“脯氨酸样”代谢物：-氨基乙酰丙酸，在急性间歇性卟啉症中积累，这是一种与精神病和癫痫发作相关的疾病；l -酚酸，在吡哆醇（维生素B6）依赖性癫痫中积累，这是一种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。我们假设，在这些具有重叠神经精神症状的疾病中，这些模拟gaba代谢物在中枢神经系统内的积累可能会破坏正常的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GABA系统组成部分正常的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提供重要的初步见解

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.