Membrane properties of neurons controlling jaw function in a mouse model of ALS

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种进行性、致死性神经退行性疾病，最终导致上下运动神经元变性。大约10-15%的确诊ALS病例是遗传性的（熟悉型ALS）（FALS），而其余的是散发性的。临床上，该病的特征是四肢肌肉无力、萎缩和肌束震颤，以及吞咽和咀嚼困难。患者通常在诊断后3-5年内死于呼吸衰竭。这项研究的长期目标是确定导致ALS运动神经元功能和发病机制进行性丧失的细胞机制，并建立可用于开发多方面治疗方法以延缓变性进展的靶点。我们的直接目标，使用小鼠模型ALS（SOD 1小鼠）和电生理，以及线粒体和钙成像方法，是测试我们的工作假设，即突触前改变的内在电压门控的钙和/或钾通道在三叉神经运动神经元和突触前三叉神经本体感受初级传入神经元同时发生，并有助于超兴奋先前观察到的SOD 1突变小鼠。该信息是重要的，因为突触前和突触后靶神经元中内在离子通道功能的同时变化可能1）是启动疾病过程的复杂联合信号，以及2）产生突触前或突触后膜兴奋性的增加，其导致在ALS患者中观察到的痉挛和肌束震颤，以及3）触发导致脆弱靶神经元（三叉神经）中的钙兴奋毒性的过程。对ALS抗性外展肌运动神经元的平行研究将提供有关运动神经元对疾病过程的不同脆弱性的机制的有价值的信息。我们的实验将使用一个独特的脑干切片制备，包含在附近，三叉神经和外展神经运动神经元，以及感觉Mes V神经元细胞体。将获得对照和SOD 1突变动物中不同神经元类型之间的钾和钙通道特性变化、钙浓度变化和线粒体功能评估的直接比较，并提供关于ALS发病机制的有价值的信息。 公共卫生相关性：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，临床上以肌肉力量的进行性丧失和吞咽和咀嚼困难为特征，目前尚无治愈方法。神经元离子通道产生适当的感觉运动功能所必需的电信号，这些通道的异常可导致各种疾病。使用ALS动物模型检测离子通道功能的症状前变化可能导致鉴定可用于开发治疗策略以延长ALS患者寿命的生理靶点。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that ends with degeneration in both upper and lower motoneurons. Approximately 10-15% of the diagnosed ALS cases are inherited, (familiar ALS) (FALS), while the remaining are sporadic. Clinically, the disease is characterized by muscle weakness, atrophy and fasciculations in the limbs and difficulty in swallowing and chewing. Patients typically die within 3-5 years of diagnosis due to respiratory failure. The long-term goals of this research are to determine the cellular mechanisms that lead to the progressive loss of motoneuronal function and pathogenesis of ALS, and to establish targets that can be used to develop a multifaceted therapeutic approach to delaying the progression of the degeneration. Our immediate goal, using a mouse model of ALS (SOD1 mice) and electrophysiological, as well as mitochondrial and calcium imaging methods, is to test our working hypothesis that presymptomatic alterations of intrinsic voltage-gated calcium and/or potassium channels in trigeminal motoneurons and presynaptic trigeminal proprioceptive primary afferent neurons occur simultaneously, and contribute to the hyperexcitability previously observed in SOD1 mutant mice. This information is important because simultaneous changes in intrinsic ion channel function in pre- and postsynaptic target neurons could 1) be complex conjoint signals to initiate the disease process, and 2) produce an increase in pre- or postsynaptic membrane excitability that leads to the observed spasticity and fasciculations observed in ALS patients, as well as 3) trigger the processes that lead to calcium excitotoxicity in vulnerable target neurons (trigeminal). Parallel studies on ALS resistant abducens motoneurons will provide valuable information on the mechanism(s) responsible for the differential vulnerability of motoneurons to the disease process. Our experiments will use a unique brainstem slice preparation that contains in close proximity, trigeminal and abducens motoneurons, as well as sensory Mes V neuronal cell bodies. Direct comparisons of changes in potassium and calcium channel properties, calcium concentration changes and assessment of mitochondrial function between different neuron types in control and SOD1 mutant animals will be obtained and provide valuable information on the pathogenesis of the ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neuro-degenerative disease clinically characterized by progressive loss of muscle force and difficulty in swallowing and chewing, for which there is no cure. Neuronal ion channels produce the electrical signals necessary for proper sensory-motor function and abnormalities in these channels can lead to a variety of disorders. Detection of presymptomatic changes in ion channel function using animal models for ALS could lead to identification of physiological targets that can be used in development of therapeutic strategies to prolong life of those with ALS.