Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0709, USA.
J Neurosci. 2010 Feb 17;30(7):2513-20. doi: 10.1523/JNEUROSCI.5840-09.2010.
Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD.
神经元可塑性缺陷是胎儿酒精谱系障碍 (FASD) 中许多神经行为问题的基础。最近，我们发现，妊娠晚期酒精暴露会导致眼优势 (OD) 可塑性持续中断。例如，几天的单眼剥夺会导致正常动物对剥夺眼反应的皮质区域明显减少，但在早期暴露于酒精的雪貂中则不会。如果在单眼剥夺期间用磷酸二酯酶 1 (PDE1) 抑制剂治疗酒精暴露的动物，这种可塑性缺陷可以逆转。PDE1 抑制可以增加 cAMP 和 cGMP 水平，激活转录因子，如 cAMP 反应元件结合蛋白 (CREB) 和血清反应因子 (SRF)。SRF 对于许多可塑性过程很重要，如 LTP、 LTD、棘突运动和轴突寻路。在这里，我们试图在单眼剥夺期间使用辛德毕斯病毒载体表达组成型激活形式的 SRF 来挽救酒精处理的雪貂的 OD 可塑性。通过使用内在信号的光学成像和单细胞记录，我们观察到，过表达组成型激活形式的 SRF，但不是其显性负性形式或 GFP，都可以恢复酒精处理动物的 OD 可塑性。令人惊讶的是，这种恢复在初级视觉皮层的整个范围内都观察到，并且大多数被病毒感染的细胞对 GFAP 呈阳性，而不是 NeuN。这一发现表明，在 FASD 模型中，星形胶质细胞中 SRF 的过表达可能会减少神经元可塑性缺陷。
