Lambot Laurie, Chaves Rodriguez Elena, Houtteman Delphine, Li Yuquing, Schiffmann Serge N, Gall David, de Kerchove d'Exaerde Alban
Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida 32610.
J Neurosci. 2016 May 4;36(18):4976-92. doi: 10.1523/JNEUROSCI.2717-15.2016.
The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected.
The striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic plasticity essential for sustaining these behaviors, we generated a mouse model lacking NMDA-Rs specifically in striatopallidal neurons. To our knowledge, this is the first time that a specific deletion of inhibitory, indirect pathway medium-sized spiny neuron (iMSN) NMDA-Rs has been used to address the role of these receptors in the inhibitory pathway. Importantly, we found that this specific deletion led to a significant reduction in the number and strength of the cortico-iMSN synapses, which resulted in the significant impairments of behaviors orchestrated by the basal ganglia. Our findings indicate that the NMDA-Rs of the indirect pathway are essential for habituation, action selection, and goal-directed learning.
基底神经节（BG）控制动作选择、运动程序、习惯和目标导向学习。纹状体是BG的主要输入结构，主要由中型多棘神经元（MSN）组成。从这些空间上相互混合的MSN产生两种抑制性输出，形成两条主要的传出通路，即直接通路和间接通路。黑质纹状体MSN产生激活的直接通路MSN，而苍白球纹状体MSN产生抑制性间接通路（iMSN）。BG输出核整合来自两条通路的信息，以微调运动程序并习得复杂的习惯和技能。因此，两条通路之间的平衡活动对于BG的和谐功能至关重要。尽管关于谷氨酸N-甲基-D-天冬氨酸受体（NMDA-Rs）在纹状体中的作用的知识有所增加，但对NMDA-R iMSN的具体功能仍缺乏了解。为此，我们生成了一种条件性敲除小鼠，以研究NMDA-R在间接通路中的功能。在细胞水平上，iMSN中GluN1的缺失导致兴奋性皮质纹状体苍白球突触的数量和强度减少。随后输入整合的缩减导致BG输出功能失调性变化，表现为习惯化减少、目标导向学习延迟、缺乏联想行为以及动作选择或技能学习受损。iMSN中NMDA-R的缺失导致苍白球纹状体神经元的突触强度降低，这进而可能导致直接和间接MSN通路之间的整合失衡，使小鼠对环境变化不那么敏感。因此，它们基于环境经验进行学习和适应的能力受到显著影响。
纹状体通过两条拮抗通路的协同激活来控制习惯、运动和目标导向行为。鉴于NMDA受体（NMDA-Rs）在维持这些行为所必需的突触可塑性中起关键作用，我们生成了一种在苍白球纹状体神经元中特异性缺乏NMDA-Rs的小鼠模型。据我们所知，这是首次使用抑制性间接通路中型多棘神经元（iMSN）NMDA-Rs的特异性缺失来研究这些受体在抑制性通路中的作用。重要的是，我们发现这种特异性缺失导致皮质-iMSN突触的数量和强度显著减少，这导致基底神经节协调的行为出现显著损伤。我们的研究结果表明，间接通路的NMDA-Rs对于习惯化、动作选择和目标导向学习至关重要。
