EPILEPTIFORM EEG ACTIVITY AND PRE-PULSE INHIBITION IN PHENYLKETONURIA

苯丙酮尿症中癫痫样脑电图活动和前脉冲抑制

• 批准号: 7717115
• 负责人: ANATOLY E MARTYNYUK
• 金额: $ 1.08万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7717115
• 关键词: Acute; Blood - brain barrier anatomy; Brain; Computer Retrieval of Information on Scientific Projects Database; Depressed mood; Epilepsy; Functional disorder; Funding; Genes; Glutamate Receptor; Glutamates; Glutathione S-Transferase; Grant; Hyperphenylalaninaemias; In Vitro; Inborn Errors of Metabolism; Institution; Intervention; Mental Retardation; Motor; Mus; Mutation; Neurologic; Neuropsychology; Patients; Phenylalanine; Phenylalanine Hydroxylase; Physiologic pulse; Plasma; Pliability; Prosencephalon; Pulse taking; Range; Research; Research Personnel; Resources; Role; Schizophrenia; Seizures; Side; Source; Stimulus; Symptoms; Synaptic Transmission; United States National Institutes of Health; Withdrawal; density; dietary control; executive function; in vivo

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phenylketonuria PKU is one of the most common inborn errors of metabolism. The underlying mutations in the phenylalanine hydroxylase Pah gene cause an accumulation of phenylalanine Phe and its metabolites on both sides of the blood-brain barrier, resulting in a spectrum of neurologic and neuropsychologic symptoms. These symptoms are related to the degree of dietary control and range from mental retardation and seizures in classical PKU to deficits in attentional flexibility and executive function even in early-treated PKU patients. The mechanism whereby hyperphenylalaninemia results in brain dysfunction are not known. The expression and density of glutamate receptors, were significantly increased in the forebrains of PKU Pahenu2 mice, providing evidence that glutamatergic synaptic transmission in PKU brain is impaired. One manifestation of PKU shared by schizophrenia is the inability to ignore irrelevant or redundant stimuli. This is referred to as a sensori-motor gating deficit and may be a component underlying deficits in executive function. A sensori-motor gating deficit can be assessed by using the pre-pulse inhibition PPI paradigm. Interventions that depress GST have been shown to increase PPI. Given the pivotal role of L-Phe for the degree to which classical PKU manifests in vivo and given that acute application of L-Phe impairs GST whereas withdrawal elicits excitatory phenomena in vitro, we hypothesize that changes in L-Phe plasma concentrations parallel changes excitatory epileptiform electroencephalographic activity, changes in PPI, and changes in executive function in PKU patients, who alter dietary control.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 苯丙酮尿症是最常见的先天性代谢缺陷之一。苯丙氨酸羟化酶Pah基因的潜在突变导致苯丙氨酸Phe及其代谢产物在血脑屏障两侧的积累，导致一系列神经学和神经心理学症状。 这些症状与饮食控制的程度有关，范围从典型PKU的精神发育迟滞和癫痫发作到即使在早期治疗的PKU患者中注意力灵活性和执行功能的缺陷。 高苯丙氨酸血症导致脑功能障碍的机制尚不清楚。 PKU Pahenu 2小鼠前脑中谷氨酸受体的表达和密度显著增加，提供了PKU脑中谷氨酸能突触传递受损的证据。 精神分裂症共有的PKU的一个表现是无法忽视无关或多余的刺激。 这被称为感觉-运动门控缺陷，可能是执行功能缺陷的一个组成部分。感觉-运动门控缺陷可以通过使用前脉冲抑制PPI范例来评估。抑制商品及服务税的干预措施已被证明会增加PPI。考虑到L-Phe对经典PKU在体内表现的程度的关键作用，并考虑到L-Phe的急性应用损害GST，而在体外戒断激发兴奋现象，我们假设L-Phe血浆浓度的变化平行于改变饮食控制的PKU患者的兴奋性癫痫样脑电图活动、PPI变化和执行功能变化。