The role of Nucleus Accumbens and Calcium-Permeable AMPA Receptors in the Pathophysiology of Huntington's Disease

摘要 亨廷顿氏病（HD）是一种遗传性神经退行性疾病， HTT基因的CAG重复序列。HD的精神症状，包括冷漠、抑郁、情绪 摆动和易怒，伴随并往往先于运动异常的发作，但很差 不被理解，不被充分对待。HD患者的主要组织病理学是中- 纹状体中的大小的多刺神经元（MSN）和大脑皮层中的锥体神经元。令人惊讶的是， 虽然背外侧纹状体（一个参与运动控制的区域）的作用已被广泛研究， 在HD研究中，涉及腹内侧纹状体的一个区域--中脑核（NAc）的作用 在奖赏知觉、情绪调节和动机突显的认知过程中， 在很大程度上被忽视。因此，本提案的第一个目标将是审查职能进展情况， 在两种HD小鼠模型中，R6/2（一种HD小鼠模型）的NAc MSN和形态学异常。 青少年HD）和Q175（成人发病HD的模型）。我们假设在NAc中的MSN， 特别是表达多巴胺D2受体的那些，将显示早期电生理学和 形态异常NAc接受来自内侧前额叶的突触能投射 皮质（mPFC），一个在动机中起关键作用的区域，当功能失调时，可能导致 精神症状。此外，在病理条件下，mPFC-NAc突触经历 由非典型Ca 2+渗透性（CP）-AMPA受体插入支持的异常可塑性变化 （AMPAR）。虽然CP-AMPAR介导兴奋性毒性，并已被假设为发挥关键作用， 在神经退行性疾病中的作用，这一假设尚未在HD中进行系统性检验。 因此，本提案的第二个目标将审查CP-AMPAR在mPFC-NAc中的作用。 突触在MSN功能障碍的NAc。我们假设NAc MSN，特别是那些 表达D2受体，在HD中逐渐受到影响， 通过使突触CP-AMPAR失能而在mPFC-NAc投射中发生的异常可以恢复 NAc功能正常，延迟即将发生的细胞丢失。为了验证这些假设，我们将使用切片 用于检测D1/D2受体表达的电生理学和形态学变化的制剂 在NAC的MSN。此外，我们将使用光遗传学方法分离并尝试恢复 mPFC-NAc投影中的正常通信。最后，NAC和CP的参与- HD相关精神症状中的AMPAR（例如，动机缺陷）将被证实， 行为测量和神经药理学操作。我们的发现将对 缓解精神症状的进展，从而提供新的治疗工具， 改善HD患者的生活质量。

Abstract Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an anomalous expansion of CAG repeats in the HTT gene. Psychiatric symptoms in HD, including apathy, depression, mood swings and irritability, accompany and often precede the onset of motor abnormalities, but are poorly understood and insufficiently treated. The major histopathology in HD patients is the loss of medium- sized spiny neurons (MSNs) in the striatum and pyramidal neurons in the cerebral cortex. Surprisingly, while the role of the dorsolateral striatum, a region involved in motor control, has been extensively studied in HD, the role of the nucleus accumbens (NAc), a region of the ventromedial striatum involved in the cognitive processing of reward perception, emotion regulation, and motivational salience, has been largely neglected. Thus, the first aim of this proposal will examine the progression of functional and morphological abnormalities in NAc MSNs in two mouse models of HD, the R6/2 (a model of juvenile HD) and the Q175 (a model of adult-onset HD). We hypothesize that MSNs in the NAc, particularly those expressing dopamine D2 receptors, will display early electrophysiological and morphological abnormalities. The NAc receives glutamatergic projections from the medial prefrontal cortex (mPFC), a region that plays a critical role in motivation and, when dysfunctional, can lead to psychiatric symptoms. Additionally, in pathological conditions, the mPFC-NAc synapses undergo aberrant plastic changes supported by the insertion of atypical Ca2+-permeable (CP)-AMPA receptors (AMPARs). Although CP-AMPARs mediate excitotoxicity and have been hypothesized to play a pivotal role in neurodegenerative disorders, this hypothesis has not been tested systematically in HD. Therefore, the second aim of this proposal will examine the role of CP-AMPARs at mPFC-NAc synapses in MSN dysfunction in the NAc. We hypothesize that the NAc MSNs, particularly those expressing D2 receptors, become progressively affected in HD and that reverting neuronal abnormalities occurring in the mPFC-NAc projections by disabling synaptic CP-AMPARs can restore NAc normal function and delay impending cell loss. To test these hypotheses, we will use the slice preparation to examine electrophysiological and morphological changes in D1/D2 receptor-expressing MSNs in the NAc. Furthermore, we will use optogenetic approaches to isolate and attempt to restore normal communication in the mPFC-NAc projection. Finally, the involvement of the NAc and CP- AMPARs in HD-associated psychiatric symptoms (e.g., motivation deficits) will be confirmed by behavioral measurements and neuropharmacological manipulations. Our findings will be crucial to alleviate the progression of psychiatric symptoms, thereby providing novel therapeutic tools in order to improve the quality of life of HD patients.