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

基本信息

批准号：
7605505
负责人：
ANATOLY E MARTYNYUK
金额：
$ 0.05万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-23 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7605505
关键词：
Acute Affect Blood - brain barrier anatomy Brain Classical phenylketonuria Computer Retrieval of Information on Scientific Projects Database Data Depressed mood Epilepsy Functional disorder Funding GABA Receptor Genes Glutamate Receptor Glutamates Grant Hippocampus (Brain)Hyperphenylalaninaemias In Vitro Inborn Errors of Metabolism Institution Intervention Literature Mental Depression Mental Retardation Molecular Motor Mus Mutation Neurologic Neurons Neuropsychology Patients Phenylalanine Phenylalanine Hydroxylase Physiologic pulse Plasma Pliability Prosencephalon Pulse taking Range Rattus Research Research Personnel Resources Role Schizophrenia Seizures Side Site Source Stimulus Symptoms Synaptic Transmission United States National Institutes of Health Withdrawal base density dietary control executive function in vivo postsynaptic presynaptic response

项目摘要

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.

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。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。我们最近证明，在 PKU 大脑中发现的一系列浓度下，急性应用 L-Phe 可选择性抑制大鼠和小鼠海马和大脑皮质培养神经元突触前和突触后位点的谷氨酸突触传递 (GST)，但不影响γ-氨基丁酸（GABA）能活性。与体外选择性抑制 GST 一致，PKU (Pahenu2) 小鼠前脑中谷氨酸受体（而非 GABA 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。这些结果和文献数据表明，谷氨酸能突触传递受损是 PKU 神经系统和神经心理学表现的基础（或促成）。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 是指当刺激（脉冲）紧接在较弱的预刺激（预脉冲）之前时，对足够强烈以引发惊吓反应的刺激（脉冲）的反应减弱。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。