Hutton Scott R, Otis James M, Kim Erin M, Lamsal Yashna, Stuber Garret D, Snider William D
Neuroscience Center.
Department of Psychiatry, and.
J Neurosci. 2017 Aug 23;37(34):8102-8115. doi: 10.1523/JNEUROSCI.0473-17.2017. Epub 2017 Jul 21.
The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs. Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.
细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）细胞内信号通路被认为是通过调节突触可塑性和基因转录来调控纹状体活动的关键因子。然而，先前对纹状体ERK/MAPK功能的研究结果相互矛盾。此外，由于依赖全身给药的药理学ERK/MAPK抑制剂以及使用仅部分降低总ERK/MAPK活性的遗传模型，这些研究尚未阐明ERK/MAPK信号在细胞类型特异性方面的作用。在此，我们构建了小鼠模型，其中在两类不同的中型多棘神经元（MSN）中ERK/MAPK信号均被完全消除。D1R-MSNs（直接通路）中ERK/MAPK的缺失导致运动行为减少、体重增加降低以及出生后早期死亡。相反，D2R-MSNs（间接通路）中ERK/MAPK信号的缺失导致显著的运动亢进表型。ERK/MAPK缺陷的D2R-MSNs即使在药理学刺激后，其树突棘密度也显著降低，电兴奋性明显受到抑制，且与活动相关的基因表达也受到抑制。我们的结果表明ERK/MAPK信号在控制纹状体直接和间接通路的运动功能中具有重要作用。我们的数据进一步表明ERK在维持D2R-MSNs的兴奋性和可塑性方面起着关键作用。ERK/MAPK活性的改变与药物滥用以及神经精神和运动障碍有关。然而，缺乏定义ERK/MAPK信号在纹状体相关神经生理学和行为中功能的遗传学证据。我们表明ERK/MAPK信号的缺失会导致运动功能的通路特异性改变、神经元兴奋性降低以及中型多棘神经元无法调节活动诱导的基因表达。我们的结果强调了ERK/MAPK通路在人类运动障碍中的潜在重要性。
