McMaster Integrative Neuroscience Discovery and Study (MiNDS) Program, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
McMaster Integrative Neuroscience Discovery and Study (MiNDS) Program, McMaster University, Hamilton, Ontario L8S 4K1, Canada; Department of Psychology, Neuroscience & Behavior, McMaster University, Hamilton, Ontario L8S 4K1, Canada; Department of Psychology, University of Toronto Mississauga, Mississauga, L5L 1C6, ON.
eNeuro. 2016 Jan 4;2(6). doi: 10.1523/ENEURO.0126-15.2015. eCollection 2015 Nov-Dec.
Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity.
氟西汀已成为治疗持续性弱视的一种新方法，因为在成年动物中，它恢复了类似关键期的眼优势可塑性，并促进了视力的恢复。然而，将这些结果从动物模型转化到临床应用一直具有挑战性，因为人们对这种选择性 5-羟色胺再摄取抑制剂如何影响谷氨酸能和 GABA 能突触机制（这些机制对经验依赖性可塑性至关重要）缺乏了解。一个吸引人的假设是，氟西汀通过将突触机制向更幼稚的状态转变来重现类似关键期的状态。为了验证这一点，我们研究了氟西汀单独或与视觉剥夺（单眼剥夺）联合治疗对一组高度保守的突触前和突触后蛋白（突触素、突触小体相关蛋白、VGLUT1、VGAT、PSD-95、神经胶质原纤维酸性蛋白、GluN1、GluA2、GluN2B、GluN2A、GABAAα1、GABAAα3）的影响。我们没有发现证据表明氟西汀将蛋白质的数量或平衡转移到类似关键期的状态。相反，它使平衡更倾向于更成熟的亚基（GluN2A、GABAAα1）。此外，当氟西汀与 MD 联合使用时，它通过使成年 MD 中发现的谷氨酸能增益正常化，创造了一种类似于神经保护的环境。总之，我们的结果表明，氟西汀治疗创造了一种以 GluN2A 和 GABAAα1 依赖性可塑性为主导的新型突触环境。
