EPILEPTIFORM EEG ACTIVITY AND PRE-PULSE INHIBITION IN PHENYLKETONURIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 苯丙酮尿症PKU是最常见的先天性代谢疾病之一。苯丙氨酸羟基酶Pah基因的潜在突变导致苯丙氨酸苯丙氨酸及其代谢产物在血脑屏障两侧积聚，导致一系列神经和神经心理症状。这些症状与饮食控制的程度有关，从经典PKU中的智力低下和癫痫发作到注意力灵活性和执行功能的缺陷，甚至在早期接受治疗的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小鼠前脑内谷氨酸受体的表达和密度显著增加，为PKU脑内谷氨酸能突触传递功能受损提供了证据。 精神分裂症的PKU的一个共同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潜在组成部分。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。抑制GST的干预措施已被证明会提高PPI。鉴于L-苯丙氨酸在经典苯丙酮尿症体内表现的关键作用，以及在体外急性应用L-苯丙氨酸损害谷胱甘肽转移酶而停药引起兴奋现象，我们假设L-苯丙氨酸血药浓度的变化平行地改变了兴奋性癫痫样脑电活动、PPI的变化和执行功能的变化，从而改变了饮食控制。

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.