EPILEPTIFORM EEG ACTIVITY AND PRE-PULSE INHIBITION IN PHENYLKETONURIA

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（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）及其代谢产物在血脑屏障两侧的积累，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，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。 尽管在了解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尚不清楚。 我们最近已经证明，急性应用L-Phe，在PKU脑中发现的浓度范围内，选择性地抑制大鼠和小鼠海马和海马皮层培养的神经元在突触前和突触后位点的GABA能突触传递（GST），但不影响γ-氨基丁酸（GABA）能活性。 与体外GST选择性抑制一致，PKU（Pahenu 2）小鼠前脑中谷氨酸受体（而非GABA受体）的表达和密度显著增加，这提供了PKU脑中谷氨酸能突触传递受损的证据。这些结果和文献数据表明，受损的突触能传递的基础（或有助于）PKU的神经和神经心理学表现。 精神分裂症所共有的PKU的一种表现是无法忽视不相关或多余的刺激。 这种能力丧失被称为感觉-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。PPI指的是对刺激（脉冲）的反应降低，该刺激（脉冲）的强度足以在该刺激之前立即出现较弱的前刺激（前脉冲）时引起惊吓反应。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。

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.