Subregion-Specific Regulation of Dopamine D1 Receptor Signaling in the Striatum: Implication for L-DOPA-Induced Dyskinesia
Subregion-Specific Regulation of Dopamine D1 Receptor Signaling in the Striatum: Implication for L-DOPA-Induced Dyskinesia
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DOI：
10.1523/jneurosci.0373-21.2021
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发表时间：
2021-06
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通讯作者：
Keita Sugiyama;M. Kuroiwa;T. Shuto;Y. Ohnishi;Y. Kawahara;Yuta Miyamoto;T. Fukuda;A. Nishi
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作者：
Keita Sugiyama;M. Kuroiwa;T. Shuto;Y. Ohnishi;Y. Kawahara;Yuta Miyamoto;T. Fukuda;A. Nishi
纹状体是基底神经节的主要结构。纹状体接收来自不同皮质区域的输入，其亚区在运动和情绪功能中起着不同的作用。最近，基于皮质纹状体连通性和纹状体-基质区隔的纹状体图谱被开发出来，我们能够将纹状体细分为七个亚区。多巴胺能调节中棘神经元的兴奋性对纹状体功能至关重要。在这项研究中，我们研究了雄性小鼠纹状体七个亚区多巴胺信号的功能特性。通过监测包括DARPP-32在内的PKA底物在小鼠纹状体切片中的磷酸化，我们确定了两个D1受体信号传导低的亚区：中间/吻侧的背外侧部分（DL-IR）和中间/尾侧部分（IC）。磷酸化二酯酶（PDE）10A和毒菌碱M4受体维持了两个亚区D1受体的低信号。在6-羟多巴胺（6-OHDA）诱导的半帕金森病动物模型中，D1受体信号在包括DL-IR在内的几乎所有亚区都上调，但在IC中没有上调。当l -多巴诱导的运动障碍（LID）发生时，IC中的D1受体信号上调，并与LID的严重程度相关。我们的研究结果表明，纹状体的功能是通过对多巴胺D1受体信号的亚区域特异性调节来维持的，而IC中D1受体信号的异常激活参与了LID。未来对纹状体IC中D1受体信号的研究将促进LID新疗法的发展。基于皮质纹状体连通性和纹状体-基质区隔的纹状体定位的最新进展使我们能够将纹状体细分为七个亚区。对七个亚区D1受体信号传导的分析确定了两个独特的D1受体信号传导低的亚区：中间/吻侧的背外侧部分（DL-IR）和中间/尾侧部分（IC）。IC中D1受体信号的异常激活与左旋多巴诱导的运动障碍（LID）有关。以往的LID研究主要集中在DL-IR上，而对纹状体的IC研究较少。未来的研究需要阐明IC中D1受体信号的异常，以开发新的LID治疗方法。
The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID. SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.