Danilov Camelia A, Steward Oswald
Reeve-Irvine Research Center, University of California, Irvine School of Medicine, Irvine, CA 92697, USA.
Reeve-Irvine Research Center, University of California, Irvine School of Medicine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine School of Medicine, Irvine, CA 92697, USA; Department of Neurobiology & Behavior, University of California, Irvine School of Medicine, Irvine, CA 92697, USA; Department of Neurosurgery, University of California Irvine, School of Medicine, Irvine, CA 92697, USA.
Exp Neurol. 2015 Apr;266:147-60. doi: 10.1016/j.expneurol.2015.02.012. Epub 2015 Feb 20.
Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTEN(loxP/loxP) mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno-associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion and into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery.
先前的研究表明,新生小鼠中磷酸酶和张力蛋白同源物(PTEN)的条件性基因缺失可增强成年小鼠脊髓损伤(SCI)后轴突的再生能力。在此,我们评估了SCI后在成年神经元中删除PTEN是否也有效,以及再生生长增强是否伴随着自主运动功能恢复的增强。PTEN(loxP/loxP)小鼠在颈5(C5)水平接受中度挫伤。一组在感觉运动皮层单侧注射表达CRE的腺相关病毒(AAV-CRE);对照组注射表达绿色荧光蛋白的载体(AAV-GFP)或仅接受损伤(不注射载体)。SCI后14周使用握力计(GSM)和悬挂任务测试前肢功能。通过将微型红宝石BDA注入感觉运动皮层来追踪皮质脊髓束(CST)。SCI后立即前肢抓握能力严重受损,但随时间缓慢恢复。与AAV-GFP组或仅损伤组相比,PTEN缺失小鼠的恢复程度明显更大。BDA束追踪显示,与对照组相比,PTEN缺失组尾段中BDA标记的轴突数量明显更多。此外,在PTEN缺失组中,有丰富的侧支从损伤部位前方的主束延伸到损伤部位的瘢痕组织内和周围。这些结果表明,SCI后不久在成年小鼠中删除PTEN可增强CST轴突的再生生长和前肢运动功能恢复。