Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, Indiana 46202.
eNeuro. 2022 Apr 20;9(2). doi: 10.1523/ENEURO.0119-22.2022. Print 2022 Mar-Apr.
The opioid crisis has contributed to a growing population of children exposed to opioids during fetal development; however, many of the long-term effects of opioid exposure on development are unknown. We previously demonstrated that opioids have deleterious effects on endocannabinoid plasticity at glutamate synapses in the dorsal striatum of adolescent rodents, but it is unclear whether prenatal opioid exposure produces similar neuroadaptations. Using a mouse model of prenatal methadone exposure (PME), we performed proteomics, phosphoproteomics, and patch-clamp electrophysiology in the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) to examine synaptic functioning in adolescent PME offspring. PME impacted the proteome and phosphoproteome in a region- and sex-dependent manner. Many proteins and phosphorylated proteins associated with glutamate transmission were differentially abundant in PME offspring, which was associated with reduced glutamate release in the DLS and altered the rise time of excitatory events in the DMS. Similarly, the intrinsic excitability properties of DMS neurons were significantly affected by PME. Last, pathway analyses revealed an enrichment in retrograde endocannabinoid signaling in the DLS, but not in the DMS, of males. Electrophysiology studies confirmed that endocannabinoid-mediated synaptic depression was impaired in the DLS, but not DMS, of PME-males. These results indicate that PME induces persistent neuroadaptations in the dorsal striatum and could contribute to the aberrant behavioral development described in offspring with prenatal opioid exposure.
阿片类药物危机导致越来越多的胎儿在胎儿发育过程中接触到阿片类药物；然而，阿片类药物暴露对发育的许多长期影响尚不清楚。我们之前的研究表明，阿片类药物对青少年啮齿动物背侧纹状体谷氨酸突触的内源性大麻素可塑性有有害影响，但尚不清楚产前阿片类药物暴露是否会产生类似的神经适应性变化。使用产前美沙酮暴露（PME）的小鼠模型，我们在背外侧纹状体（DLS）和背内侧纹状体（DMS）中进行了蛋白质组学、磷酸蛋白质组学和膜片钳电生理学研究，以检查青少年 PME 后代的突触功能。PME 以区域和性别依赖的方式影响蛋白质组和磷酸蛋白质组。许多与谷氨酸传递相关的蛋白质和磷酸化蛋白质在 PME 后代中丰度不同，这与 DLS 中谷氨酸释放减少以及 DMS 中兴奋性事件上升时间改变有关。同样，PME 显著影响 DMS 神经元的固有兴奋性特性。最后，通路分析显示 DLS 中逆行内源性大麻素信号转导富集，但 DMS 中没有富集。电生理学研究证实，DLS 中的内源性大麻素介导的突触抑制在 PME 雄性中受损，但在 DMS 中没有受损。这些结果表明，PME 会导致背侧纹状体中持续的神经适应性变化，并可能导致产前阿片类药物暴露的后代中描述的异常行为发育。
