Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity

IF 6.7 1区 医学 Q1 NEUROSCIENCES
Sarah Chevalier, Mélina Decourt, Maureen Francheteau, François Nicol, Anaïs Balbous, Pierre-Olivier Fernagut, Marianne Benoit-Marand
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Abstract

Parkinson’s disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations following neurodegeneration or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. This study investigated the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity, and markers of synaptic plasticity. Bilateral nigrostriatal degeneration was induced by viral-mediated expression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed, and spike probability in response to OFC stimulation was measured before and after high-frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB protein levels. Nigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had the opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB in the DMS. This study demonstrates that nigral dopaminergic loss and PPX both contribute to alter frontostriatal transmission, precluding adequate information processing in associative basal ganglia loops as a gateway for the development of non-motor symptoms or non-motor side effects of DRT.

Abstract Image

α-突触核蛋白诱导的黑质变性和普拉克索治疗会破坏前额纹状体的可塑性
帕金森病的特征是黑质紧密团(SNc)多巴胺能神经元变性,导致运动和认知症状。在运动网络中描述了神经变性或多巴胺替代疗法(DRT)后的许多细胞和分子适应性,但对基底节联想环路却知之甚少。本研究调查了黑质变性和普拉克索(PPX)对眶额皮层(OFC)神经元活动、前额纹可塑性和突触可塑性标记物的影响。病毒介导的人类突变α-突触核蛋白在SNc中的表达诱发了双侧黑质变性。对麻醉大鼠进行了并细胞记录,以评估OFC的神经元活动。对背内侧纹状体(DMS)进行了记录,并在高频刺激(HFS)前后测量了对OFC刺激的尖峰概率。尸检分析包括黑质神经变性、BDNF和TrkB蛋白水平的立体学评估。黑质神经变性导致 OFC 神经元的发射模式发生改变,而 PPX 可使其恢复正常。OFC的HFS导致DMS的尖峰概率增加,而多巴胺能损失则产生相反的效果。PPX会导致对照组大鼠HFS后的尖峰概率降低,但却无法抵消多巴胺能神经变性的影响。这些改变与DMS中BDNF和TrkB水平的降低有关。这项研究表明,黑质多巴胺能缺失和 PPX 都会改变前额纹状体的传导,从而阻碍联想基底节环路进行适当的信息处理,这是 DRT 出现非运动症状或非运动副作用的一个途径。
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来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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