Scuola Normale Superiore, Neurobiology Laboratory, CNR, Pisa, Italy.
Eur J Neurosci. 2011 Jan;33(1):49-57. doi: 10.1111/j.1460-9568.2010.07488.x. Epub 2010 Dec 12.
Cortical circuitries are highly sensitive to experience during early life but this phase of heightened plasticity decreases with development. We recently demonstrated that fluoxetine reinstates a juvenile-like form of plasticity in the adult visual system. Here we explored cellular and molecular mechanisms that underlie the occurrence of these plastic phenomena. Adult rats were intracortically treated with serotonin (5-HT) whereas long-term fluoxetine-treated rats were infused with the 5-HT(1A) -receptor antagonist WAY-100635, brain-derived neurotrophic factor (BDNF) scavenger trkB-IgG or the mitogen-activated protein kinase inhibitor U0126. Plasticity was assessed as variations of visual cortex responsiveness after unilateral eyelid suture and reverse occlusion by using an electrophysiological approach. Real-time PCR and chromatin immunoprecipitation analysis were then used to explore alterations in gene expression and modifications of chromatin structure associated with the plastic outcome caused by fluoxetine in the visual system. Local infusion of 5-HT into visual cortex restored susceptibility to monocular deprivation in adulthood whereas infusion of WAY-100635, trkB-IgG or U0126 prevented the process of plasticity reactivation in fluoxetine-treated animals. Long-term fluoxetine treatment promoted a transient increase of Bdnf expression in the visual cortex, which was paralleled by an increased histone acetylation status at Bdnf promoter regions and by decreased expression of Hdac5. Accordingly, enhancing histone acetylation levels by systemic treatment with Trichostatin-A reactivated plasticity in the adult while WAY-100635-infusion prevented epigenetic modifications in Bdnf promoter areas. The data suggest a key role for 5-HT(1A) receptor and BDNF-trkB signalling in driving a transitory epigenetic remodelling of chromatin structure that underlies the reactivation of plasticity in the visual system.
皮质回路在生命早期对经验高度敏感，但这种高可塑性阶段会随着发育而减少。我们最近证明，氟西汀可使成年视觉系统恢复类似幼年的可塑性。在这里，我们探讨了潜在的细胞和分子机制。成年大鼠皮质内给予 5-羟色胺（5-HT），而长期氟西汀治疗的大鼠则给予 5-HT1A 受体拮抗剂 WAY-100635、脑源性神经营养因子（BDNF）清除剂 trkB-IgG 或丝裂原活化蛋白激酶抑制剂 U0126。通过电生理方法评估单侧眼睑缝合和反向遮挡后视觉皮层反应的变化来评估可塑性。然后使用实时 PCR 和染色质免疫沉淀分析来探索与氟西汀在视觉系统中引起的可塑性结果相关的基因表达变化和染色质结构修饰。局部给予 5-HT 可恢复成年后对单眼剥夺的敏感性，而给予 WAY-100635、trkB-IgG 或 U0126 则可阻止氟西汀治疗动物中可塑性再激活的过程。长期氟西汀治疗可短暂增加视觉皮层中的 Bdnf 表达，这与 Bdnf 启动子区域的组蛋白乙酰化状态增加和 Hdac5 表达减少相平行。因此，通过系统给予 Trichostatin-A 增强组蛋白乙酰化水平可使成年动物恢复可塑性，而 WAY-100635 则可阻止 Bdnf 启动子区域的表观遗传修饰。数据表明，5-HT1A 受体和 BDNF-trkB 信号在驱动视觉系统中可塑性再激活的短暂表观遗传重塑的染色质结构中起着关键作用。
