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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 苯丙酮尿症 PKU 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 及其代谢物在血脑屏障两侧积累，从而导致一系列神经系统和神经心理症状。 这些症状与饮食控制程度有关，范围从经典 PKU 中的精神发育迟滞和癫痫发作，到注意力灵活性和执行功能缺陷，甚至在早期治疗的 PKU 患者中也是如此。 高苯丙氨酸血症导致脑功能障碍的机制尚不清楚。 PKU Pahenu2 小鼠前脑中谷氨酸受体的表达和密度显着增加，这提供了 PKU 大脑中谷氨酸突触传递受损的证据。 精神分裂症共有的 PKU 表现之一是无法忽视不相关或多余的刺激。 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脉冲前抑制 PPI 范例来评估。事实证明，降低 GST 的干预措施可以提高 PPI。鉴于 L-Phe 对经典 PKU 在体内表现程度的关键作用，以及急性应用 L-Phe 会损害 GST，而停药会在体外引起兴奋现象，我们假设 L-Phe 血浆浓度的变化与兴奋性的变化平行。改变饮食控制的 PKU 患者癫痫样脑电图活动、PPI 变化和执行功能变化。