Pokinko Matthew, Grant Alanna, Shahabi Florence, Dumont Yvan, Manitt Colleen, Flores Cecilia
Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montréal, Québec H4H 1R3, Canada.
Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montréal, Québec H4H 1R3, Canada; Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montréal, Québec H3A 1A1, Canada.
Neuroscience. 2017 Mar 27;346:182-189. doi: 10.1016/j.neuroscience.2017.01.009. Epub 2017 Jan 17.
Adolescence is a period during which the medial prefrontal cortex (mPFC) undergoes significant remodeling. The netrin-1 receptor, deleted in colorectal cancer (DCC), controls the extent and organization of mPFC dopamine connectivity during adolescence and in turn directs mPFC functional and structural maturation. Dcc haploinsufficiency leads to increased mPFC dopamine input, which causes improved cognitive processing and resilience to behavioral effects of stimulant drugs of abuse. Here we examine the effects of Dcc haploinsufficiency on the dynamic expression of dopamine receptors in forebrain targets of C57BL6 mice. We conducted quantitative receptor autoradiography experiments with [H]SCH-23390 or [H]raclopride to characterize D1 and D2 receptor expression in mPFC and striatal regions in male Dcc haploinsufficient and wild-type mice. We generated autoradiograms at early adolescence (PND21±1), mid-adolescence (PND35±2), and adulthood (PND75±15). C57BL6 mice exhibit overexpression and pruning of D1, but not D2, receptors in striatal regions, and a lack of dopamine receptor pruning in the mPFC. We observed age- and region-specific differences in D1 and D2 receptor density between Dcc haploinsufficient and wild-type mice. Notably, neither group shows the typical pattern of mPFC dopamine receptor pruning in adolescence, but adult haploinsufficient mice show increased D2 receptor density in the mPFC. These results show that DCC receptors contribute to the dynamic refinement of D1 and D2 receptor expression in striatal regions across adolescence. The age-dependent expression of dopamine receptor in C57BL6 mice shows marked differences from previous characterizations in rats.
青春期是内侧前额叶皮质（mPFC）经历显著重塑的时期。结直肠癌缺失基因（DCC），即一种网蛋白-1受体，在青春期控制着mPFC多巴胺连接的范围和组织，进而指导mPFC的功能和结构成熟。Dcc单倍不足会导致mPFC多巴胺输入增加，从而改善认知加工以及对滥用兴奋性药物行为效应的恢复力。在此，我们研究了Dcc单倍不足对C57BL6小鼠前脑靶点中多巴胺受体动态表达的影响。我们用[H]SCH-23390或[H]雷氯必利进行了定量受体放射自显影实验，以表征雄性Dcc单倍不足小鼠和野生型小鼠mPFC及纹状体区域中D1和D2受体的表达。我们在青春期早期（出生后第21天±1天）、青春期中期（出生后第35天±2天）和成年期（出生后第75天±15天）生成了放射自显影片。C57BL6小鼠在纹状体区域表现出D1受体的过表达和修剪，但D2受体没有，并且在mPFC中缺乏多巴胺受体修剪。我们观察到Dcc单倍不足小鼠和野生型小鼠之间D1和D2受体密度存在年龄和区域特异性差异。值得注意的是，两组在青春期均未表现出mPFC多巴胺受体修剪的典型模式，但成年单倍不足小鼠mPFC中的D2受体密度增加。这些结果表明，DCC受体有助于整个青春期纹状体区域D1和D2受体表达的动态优化。C57BL6小鼠中多巴胺受体的年龄依赖性表达与先前在大鼠中的特征表现出明显差异。
