Neurosciences Paris Seine, Institut de Biologie Paris Seine, University Pierre and Marie Curie University of Paris 06, Sorbonne Universités, Centre National pour la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Paris, France.
Neurosciences Paris Seine, Institut de Biologie Paris Seine, University Pierre and Marie Curie University of Paris 06, Sorbonne Universités, Centre National pour la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Paris, France; Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore.
Biol Psychiatry. 2017 Dec 1;82(11):806-818. doi: 10.1016/j.biopsych.2017.03.014. Epub 2017 Mar 29.
Repeated cocaine exposure produces new spine formation in striatal projection neurons (SPNs) of the nucleus accumbens. However, an acute exposure to cocaine can trigger long-lasting synaptic plasticity in SPNs leading to behavioral alterations. This raises the intriguing question as to whether a single administration of cocaine could enduringly modify striatal connectivity.
A three-dimensional morphometric analysis of presynaptic glutamatergic boutons and dendritic spines was performed on SPNs 1 hour and 1 week after a single cocaine administration. Time-lapse two-photon microscopy in adult slices was used to determine the precise molecular-events sequence responsible for the rapid spine formation.
A single injection triggered a rapid synaptogenesis and persistent increase in glutamatergic connectivity in SPNs from the shell part of the nucleus accumbens, specifically. Synapse formation occurred through clustered growth of active spines contacting pre-existing axonal boutons. Spine growth required extracellular signal-regulated kinase activation, while spine stabilization involved transcription-independent protein synthesis driven by mitogen-activated protein kinase interacting kinase-1, downstream from extracellular signal-regulated kinase. The maintenance of new spines driven by mitogen-activated protein kinase interacting kinase-1 was essential for long-term connectivity changes induced by cocaine in vivo.
Our study originally demonstrates that a single administration of cocaine is able to induce stable synaptic rewiring in the nucleus accumbens, which will likely influence responses to subsequent drug exposure. It also unravels a new functional role for cocaine-induced extracellular signal-regulated kinase pathway independently of nuclear targets. Finally, it reveals that mitogen-activated protein kinase interacting kinase-1 has a pivotal role in cocaine-induced connectivity.
反复接触可卡因会导致伏隔核（NAc）投射神经元（SPN）中新的棘突形成。然而，单次可卡因暴露会引发 SPN 中持久的突触可塑性变化，导致行为改变。这就提出了一个有趣的问题，即单次给予可卡因是否会持久地改变纹状体的连接。
在单次可卡因给药后 1 小时和 1 周，对 SPN 进行了前突触谷氨酸能末梢和树突棘的三维形态计量分析。在成年切片中使用延时双光子显微镜确定负责快速棘突形成的精确分子事件序列。
单次注射可触发快速的突触发生和持久的谷氨酸能连接增加，特别是在 NAc 的壳部 SPN 中。突触形成是通过接触预先存在的轴突末梢的活跃棘突簇状生长而发生的。棘突生长需要细胞外信号调节激酶（ERK）的激活，而棘突稳定涉及由 ERK 下游的丝裂原活化蛋白激酶相互作用激酶-1（MAPK-interacting kinase-1）驱动的非转录蛋白合成。由 MAPK-interacting kinase-1 驱动的新棘突的维持对于可卡因在体内引起的长期连接变化是必不可少的。
我们的研究最初表明，单次给予可卡因能够诱导 NAc 中稳定的突触重排，这可能会影响对随后药物暴露的反应。它还揭示了可卡因诱导的细胞外信号调节激酶途径的新功能作用，独立于核靶点。最后，它揭示了丝裂原活化蛋白激酶相互作用激酶-1在可卡因诱导的连接中具有关键作用。
