Principles of Therapy in Cerebellar Disease: Explorations in Ion Channel Mutants

描述（由申请人提供）： 今天的神经科医生有几个治疗方法，以提供病人的痛苦肢体共济失调，不平衡，视力障碍所造成的疾病的小脑。这种病人在退伍军人中很常见，而且由于在最近的军事行动中遭受的创伤性脑损伤而变得更加常见。然而，最近的发展表明，可以开发出高效的药物：两种影响神经元钾通道的药物已被证明可以改善人类和小鼠的小脑缺陷，并可能为开发更有效和更耐受的药物提供起点。然而，其治疗效果的来源是有争议的。同样，一种新的理论认为共济失调可能起源于小脑浦肯野细胞的节律紊乱，这为药物开发提供了方法，但该理论存在争议，需要更多的研究。该项目将通过阐明小脑运动功能障碍的起源和现有治疗机制为药物开发奠定更好的基础。我们专注于携带P/Q（CaV2.1）钙通道CACNA 1A基因突变的小鼠的眼球运动异常，但结果应适用于小脑功能障碍的其他原因和表现。具体目标1涉及眼动记录CACNA 1A突变体步履蹒跚，并在正常小鼠后的小脑小叶的药理学抑制，以确定在共济失调小鼠中发现的异常垂直眼位置的原因。这一结果将决定小鼠是否可以用于测试下搏性眼球震颤的治疗方法，下搏性眼球震颤是一种导致视力模糊的小脑疾病的人类表现。特定目的2通过记录正常小鼠和CACNA 1A突变型摇杆的绒球和前蚓部中的浦肯野细胞，检验钙通道突变型共济失调起源于浦肯野细胞节律紊乱的理论。这些记录的一个目的是确定是否摇杆浦肯野细胞表现出，作为节奏理论预测，节奏之间的正常动物和更严重的影响CACNA 1A突变，摇摇欲坠的中间。记录的另一个目标是重新评估CACNA 1A突变体浦肯野细胞是否在自然刺激下正常调节其放电。这一主张是节奏性理论的核心，但支持这一主张的实验可能受到采样偏差的影响。具体目标3评估了4-氨基吡啶的治疗机制，这是最近被证明对小脑疾病有一定益处的药物之一。我们将记录全身和球内注射4-氨基吡啶后蹒跚时的眼球运动。这些实验的结果将使我们能够测试已发表的推测，即氨基吡啶通过恢复正常的浦肯野细胞活性发挥其有益作用。

DESCRIPTION (provided by applicant): Today's neurologists have few therapies to offer patients suffering the limb ataxia, imbalance, and visual impairment resulting from diseases of the cerebellum. Such patients are common in the veteran population and becoming more so due to traumatic brain injuries suffered in recent military operations. Recent developments, however, suggest that highly effective drugs can be developed: Two drugs that influence neuronal potassium channels have been shown to ameliorate cerebellar deficits in humans and mice, and may provide starting points to develop more efficacious and tolerable drugs. However, the sources of their therapeutic effects are debatable. Likewise, a new theory that ataxia can originate in disturbed rhythmicity of cerebellar Purkinje cells suggests procedures for drug development, but the theory is controversial and requires more investigation. This project will lay a better groundwork for drug development by clarifying the origins of cerebellar motor dysfunction and mechanism of one existing treatment. We focus on ocular motility abnormalities in mice carrying mutations of the CACNA1A gene of the P/Q (CaV2.1) calcium channel, but the results should be applicable to other causes and manifestations of cerebellar dysfunction. Specific Aim 1 involves eye movement recordings in the CACNA1A mutant tottering, and in normal mice following pharmacological inhibition of the cerebellar flocculus, to determine the cause of the abnormal vertical eye positions found in ataxic mice. The result will determine whether mice can be used to test treatments for downbeat nystagmus, a human manifestation of cerebellar disease that results in blurred vision. Specific Aim 2 tests the theory that ataxia in calcium channel mutants originates in disturbed Purkinje cell rhythmicity, through recordings of Purkinje cells in the flocculus and anterior vermis of normal mice and the CACNA1A mutant rocker. One goal of these recordings is to determine whether rocker Purkinje cells exhibit, as the rhythmicity theory predicts, rhythmicity intermediate between that of normal animals and the more severely affected CACNA1A mutant, tottering. Another goal of the recordings is to reassess whether CACNA1A mutant Purkinje cells modulate their firing normally in response to natural stimulation. This claim is central to the rhythmicity theory, but the experiments that support the claim may have been affected by sampling bias. Specific aim 3 assesses the therapeutic mechanisms of 4- aminopyridine, one of the drugs that has recently been shown to provide some benefits in cerebellar disorders. We will record eye movements in tottering following systemic and intrafloccular injections of 4- aminopyridine. Results of these experiments will allow us to test published speculations that aminopyridines exert their beneficial effects by restoring normal Purkinje cell activity.