Laguesse Sophie, Morisot Nadege, Shin Jung Hoon, Liu Feng, Adrover Martin F, Sakhai Samuel A, Lopez Marcelo F, Phamluong Khanhky, Griffin William C, Becker Howard C, Bender Kevin J, Alvarez Veronica A, Ron Dorit
Department of Neurology, University of California, San Francisco, CA, USA.
Laboratory on Neurobiology of Compulsive Behaviors, National Institute of Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, MD, USA.
Neuron. 2017 Sep 27;96(1):145-159.e8. doi: 10.1016/j.neuron.2017.08.037. Epub 2017 Sep 8.
The mammalian target of rapamycin complex 1 (mTORC1), a transducer of local dendritic translation, participates in learning and memory processes as well as in mechanisms underlying alcohol-drinking behaviors. Using an unbiased RNA-seq approach, we identified Prosapip1 as a novel downstream target of mTORC1 whose translation and consequent synaptic protein expression are increased in the nucleus accumbens (NAc) of mice excessively consuming alcohol. We demonstrate that alcohol-dependent increases in Prosapip1 levels promote the formation of actin filaments, leading to changes in dendritic spine morphology of NAc medium spiny neurons (MSNs). We further demonstrate that Prosapip1 is required for alcohol-dependent synaptic localization of GluA2 lacking AMPA receptors in NAc shell MSNs. Finally, we present data implicating Prosapip1 in mechanisms underlying alcohol self-administration and reward. Together, these data suggest that Prosapip1 in the NAc is a molecular transducer of structural and synaptic alterations that drive and/or maintain excessive alcohol use.
雷帕霉素靶蛋白复合物1（mTORC1）是局部树突翻译的转导分子，参与学习和记忆过程以及饮酒行为的潜在机制。我们采用无偏向RNA测序方法，将Prosapip1鉴定为mTORC1的一个新的下游靶点，在过量饮酒小鼠的伏隔核（NAc）中，其翻译及随后的突触蛋白表达增加。我们证明，酒精依赖导致的Prosapip1水平升高会促进肌动蛋白丝的形成，从而导致NAc中型多棘神经元（MSN）的树突棘形态发生变化。我们进一步证明，在NAc壳层MSN中，Prosapip1是缺乏AMPA受体的GluA2酒精依赖型突触定位所必需的。最后，我们提供的数据表明Prosapip1参与了酒精自我给药和奖赏的潜在机制。总之，这些数据表明，NAc中的Prosapip1是驱动和/或维持过度饮酒的结构和突触改变的分子转导器。
