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性疾病之一。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。 尽管在理解PKU的分子基础方面取得了巨大进展，但高苯丙氨酸血症导致脑功能障碍的机制(S)尚不清楚。我们最近证实，在PKU脑中发现的浓度范围内，急性应用L-Phe选择性地抑制大鼠和小鼠海马区和大脑皮层培养神经元突触前和突触后的谷氨酸能突触传递，但不影响γ-氨基丁酸能神经元的活动。与体外选择性抑制GST一致，PKU(Pahenu2)小鼠前脑内谷氨酸受体的表达和密度显著增加，而GABA受体的表达和密度却显著增加，这为PKU脑内谷氨酸能突触传递功能受损提供了证据。这些结果和文献数据表明，谷氨酸能突触传递受损是PKU神经学和神经心理学表现的基础(或促成)。 精神分裂症所共有的PKU的一个表现是无法忽视无关或多余的刺激。这种无能被称为感觉-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-运动门控缺陷可以用脉冲前抑制(PPI)范式来评估。PPI指的是对刺激(脉冲)的反应减弱，当该刺激之前紧接着是较弱的前刺激(前脉冲)时，该刺激的强度足以引起惊吓反应。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. Despite tremendous progress in understanding the molecular basis of PKU, the mechanism(s) whereby hyperphenylalaninemia results in brain dysfunction are not known. We have recently demonstrated that acute applications of L-Phe, at a range of concentrations found in PKU brain, selectively depress glutamatergic synaptic transmission (GST) in rat and mouse hippocampal and cerebrocortical cultured neurons at pre- and postsynaptic sites, but do not affect gamma-aminobutyric (GABA)-ergic activity. Consistent with selective depression of GST in vitro, the expression and density of glutamate receptors, but not GABA receptors, were significantly increased in the forebrains of PKU (Pahenu2) mice, providing evidence that glutamatergic synaptic transmission in PKU brain is impaired. These results and literature data suggest that impaired glutamatergic synaptic transmission underlies (or contributes to) the neurologic and neuropsychologic manifestations of PKU. One manifestation of PKU that is shared by schizophrenia is the inability to ignore irrelevant or redundant stimuli. This inability 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. PPI refers to the decreased response to a stimulus (pulse) sufficiently intense to elicit a startle response when this stimulus is immediately preceded by a weaker pre-stimulus (pre-pulse). 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.