Increased persistent sodium current in SOD1 motoneurons

SOD1 运动神经元持续钠电流增加

• 批准号: 7389591
• 负责人: Charles Heckman
• 金额: $ 31.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389591
• 关键词: Action Potentials; Acute; Address; Affect; Amyotrophic Lateral Sclerosis; Animals; Antidepressive Agents; Behavior; Binding; Calcium; Cell Death; Cells; Cessation of life; Chronic; Controlled Environment; Coupled; Cultured Cells; Development; Disease; Disruption; Drug Controls; Embryo; Fluorescent Antibody Technique; GTP-Binding Proteins; Glutamates; Goals; In Vitro; Life; Link; Modeling; Molecular; Motor Neurons; Mus; Mutation; Neuromodulator; Neurotransmitters; Norepinephrine; Numbers; Onset of illness; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Preparation; Property; Prozac; Regulation; Research Personnel; Riluzole; Role; Serotonin; Slice; Sodium; Staging; Standards of Weights and Measures; Symptoms; Synapses; System; Therapeutic; Time; Transcriptional Activation; Transgenic Organisms; Up-Regulation; Work; density; design; excitotoxicity; in vivo; juvenile animal; ligand gated channel; monoamine; mouse model; mutant; novel therapeutics; programs; response; voltage; voltage gated channel

DESCRIPTION (provided by applicant): One of the leading hypotheses for motoneuron degeneration in ALS is excitotoxicity, in which excessive calcium entry leads to cell death. Most work on excitotoxicity has focused on ligand-gated channels activated by the excitatory neurotransmitter glutamate. In contrast, this proposal focuses on the possibility that ALS alters voltage-gated channels and thus alters the intrinsic excitability of the motoneuron. We have shown that a specific type of sodium (Na+) channel is markedly elevated in motoneurons cultured from a transgenic mouse model of ALS (the SOD1 model). This current is NaP, the persistent component of the total Na+ current generating the action potential. NaP is a major factor controlling the number of action potentials per time generated in response to a given amount of synaptic input. Because each action potential allows calcium to enter the cell, elevated NaP in ALS motoneurons could play a major role in excitotoxic death. The goals of this proposal are to investigate mechanisms of the aberrant upregulation of NaP in mutant SOD1 motoneurons and to assess how drugs that change NaP influence motoneuron survival. Studies are carried out in culture, in vitro in a slice preparation, and in vivo in the intact animal, all using the mutant SOD1 mouse. Aim 1 considers the issue of whether molecular subtypes or densities of the Na channels themselves change. Aim 2 focuses on potential changes in the regulation of NaP in response to acute and chronic drug administration. The monoamines serotonin and norepinephrine enhance NaP and likely play a particularly important role in its normal regulation. In Aim 3, the effects of NaP-specific drugs studied in aim 2 are evaluated for their effect on motoneuron survival both in culture and in the intact mouse. A key question addressed by Aims 2 and 3 is whether the monoamines further increase NaP above its already high levels in mutant SOD1 motoneurons. If so, then standard anti-depressant drugs may actually exacerbate motoneuron degeneration. In Aim 4, we evaluate whether, as predicted from our cell culture work, NaP is upregulated at a very early stage in life. Presence of enhanced NaP in very young animals would indicate that this aberrant property may play a significant role in the disease onset. These studies will play an essential role in determining if NaP makes an important contribution to motoneuron degeneration in ALS. Moreover, the results may prove invaluable in establishing new therapeutic strategies

描述（由申请人提供）：ALS中运动神经元变性的主要假设之一是兴奋性毒性，其中过量的钙进入导致细胞死亡。兴奋性毒性的大多数工作都集中在兴奋性神经递质谷氨酸激活的配体门控通道上。相比之下，该提案的重点是改变ALS改变电压门控通道，从而改变Motoneuron的内在兴奋性的可能性。我们已经表明，从ALS的转基因小鼠模型（SOD1模型）培养的运动神经元中，特定类型的钠（Na+）通道显着升高。该电流是小睡，是总Na+电流产生动作电位的持续分量。小睡是控制每次产生的动作电位数量的主要因素，以响应给定数量的突触输入。由于每个动作电位都允许钙进入细胞，因此ALS运动神经元的NAP升高可能在兴奋性死亡中起主要作用。该提案的目标是研究突变SOD1运动神经元中NAP异常上调的机制，并评估改变NAP的药物如何影响运动神经元的存活。研究在培养物中，在切片制剂中进行体外和完整动物的体内进行研究，所有这些都使用突变的SOD1小鼠进行。 AIM 1考虑了NA通道本身的分子亚型或密度的问题。 AIM 2重点是响应急性药物给药的NAP调节的潜在变化。单胺5-羟色胺和去甲肾上腺素增强了NAP，并可能在其正常调节中起着特别重要的作用。在AIM 3中，AIM 2中研究的NAP特异性药物的影响对它们对培养物和完整小鼠中运动神经元存活的影响进行了评估。 AIM 2和3提出的一个关键问题是，单胺是否进一步增加了突变体SOD1运动神经元已经高于其已经很高水平的NAP。如果是这样，那么标准的抗抑郁药实际上可能会加剧运动神经元变性。在AIM 4中，我们评估了在我们的细胞培养工作中预测的，在生活的早期阶段，NAP是否被上调。非常年轻的动物的午睡增强会表明这种异常特性可能在疾病发作中起重要作用。这些研究将在确定NAP是否对ALS中的运动神经元变性做出重要贡献中起着至关重要的作用。此外，结果对于建立新的治疗策略可能是无价的