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

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种进行性、致命性的神经退行性疾病，最终以上下运动神经元退行性变结束。大约10-15%的ALS诊断病例是遗传性的（熟悉性ALS），而其余的是散发性的。临床表现为四肢肌肉无力、萎缩和抽搐，吞咽和咀嚼困难。患者通常在3-5年内因呼吸衰竭而死亡。本研究的长期目标是确定导致肌萎缩侧索硬化症运动神经元功能进行性丧失和发病机制的细胞机制，并建立可用于开发多方面治疗方法的靶点，以延缓变性的进展。我们的直接目标是，使用ALS小鼠模型（SOD1小鼠）和电生理，以及线粒体和钙成像方法，验证我们的工作假设，即三叉神经运动神经元和三叉神经突触前本体感觉初级传入神经元的内在电压门控钙和/或钾通道的症状前改变同时发生，并有助于先前在SOD1突变小鼠中观察到的高兴奋性。这一信息很重要，因为突触前和突触后目标神经元固有离子通道功能的同时变化可能是1)启动疾病过程的复杂联合信号，2)产生突触前或突触后膜兴奋性的增加，导致在ALS患者中观察到的痉挛和束状，以及3)触发导致易感目标神经元（三叉神经）钙兴奋毒性的过程。对ALS抗外展运动神经元的平行研究将为运动神经元对疾病过程的不同易感性机制提供有价值的信息。我们的实验将使用一种独特的脑干切片制备，其中包含近距离的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。直接比较对照和SOD1突变动物不同神经元类型之间钾和钙通道性质的变化、钙浓度的变化和线粒体功能的评估，将为ALS的发病机制提供有价值的信息。

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.