Hippocampal Demyelination and Cognitive Dysfunction

描述(申请人提供)：多发性硬化症(MS)是一种人类中枢神经系统(CNS)的炎症性脱髓鞘疾病，是美国年轻人非创伤性神经残疾的主要原因。将MS视为一种白质疾病的经典观点最近已扩展到包括灰质脱髓鞘。灰质脱髓鞘的临床影响可能解释了为什么脑成像检测到的白质损害与MS患者的神经功能障碍相关性很差。超过50%的MS患者存在认知障碍，他们的认知障碍对生活质量的影响比身体残疾更大。最近对死后多发性硬化症大脑的研究证实，海马体脱髓鞘破坏了兴奋性突触的维持和调节记忆和学习的神经元信号级联反应的激活。海马区脱髓鞘可能是多发性硬化症患者认知功能下降的原因之一。为了证实和扩展这一假设，我们成功地建立了海马区脱髓鞘的小鼠模型，并确定这些小鼠记忆/学习减少，突触密度减少，调节记忆/学习的神经元蛋白减少，长时程增强(LTP)减少。髓鞘再生逆转了这些变化。这项提案中概述的研究旨在揭示脱髓鞘海马区神经元变化的序列，这些变化导致神经元功能障碍和记忆障碍。我们利用多学科方法将脱髓鞘海马区的行为、电生理、生化、形态和活体成像变化联系起来，并将确定重新髓鞘形成是否逆转了已有文献记载的变化。我们的研究是转化性的，应该确定可能减少或延缓多发性硬化症患者认知功能下降的潜在治疗靶点。我们的小鼠模型也应该为旨在改善多发性硬化症患者认知的治疗方法提供一个“原则证明”测试平台。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and the major cause of non-traumatic neurological disability in young adults in the USA. The classical view of MS as a white matter disease has recently been extended to include gray matter demyelination. The clinical impact of gray matter demyelination may explain why white matter lesions detected by brain imaging poorly correlate with neurological disability in MS patients. Greater than 50% of MS patients are cognitively impaired and their cognitive dysfunction has a greater impact on quality of life than physical disability. Recent studies of postmortem MS brains have established that hippocampal demyelination disrupts the maintenance of excitatory synapses and activation of neuronal signaling cascades that modulate memory and learning. Hippocampal demyelination is a likely cause of cognitive decline in MS patients. To confirm and extend this hypothesis, we have successfully developed a mouse model of hippocampal demyelination and established that these mice have reduced memory/learning, reduced synaptic densities, reduced neuronal proteins that modulate memory/learning and reduced long term potentiation (LTP). Remyelination reversed these changes. The studies outlined in this proposal are designed to unravel the sequence of neuronal changes in demyelinated hippocampi that contribute to neuronal dysfunction and memory impairment. We utilize a multidisciplinary approach to correlate behavioral, electrophysiological, biochemical, morphological, and in vivo imaging changes in demyelinated hippocampi and will determine if remyelination reverses documented changes. Our studies are translational and should identify potential therapeutic targets that could reduce or delay cognitive decline in MS patients. Our mouse model should also provide a platform for "proof of principle" testing of therapies designed to improve cognition in MS patients.