Pulimood Nisha S, Rodrigues Wandilson Dos Santos, Atkinson Devon A, Mooney Sandra M, Medina Alexandre E
University of Maryland School of Medicine, Baltimore, Maryland 21201
University of Maryland School of Medicine, Baltimore, Maryland 21201.
J Neurosci. 2017 Jul 12;37(28):6628-6637. doi: 10.1523/JNEUROSCI.0766-17.2017. Epub 2017 Jun 12.
The transcription factors CREB (cAMP response element binding factor), SRF (serum response factor), and MEF2 (myocyte enhancer factor 2) play critical roles in the mechanisms underlying neuronal plasticity. However, the role of the activation of these transcription factors in the different components of plasticity is not well known. In this study, we tested the role of CREB, SRF, and MEF2 in ocular dominance plasticity (ODP), a paradigm of activity-dependent neuronal plasticity in the visual cortex. These three proteins bind to the synaptic activity response element (SARE), an enhancer sequence found upstream of many plasticity-related genes (Kawashima et al., 2009; Rodríguez-Tornos et al., 2013), and can act cooperatively to express , a gene required for ODP (McCurry et al., 2010). We used viral-mediated gene transfer to block the transcription function of CREB, SRF, and MEF2 in the visual cortex, and measured visually evoked potentials in awake male and female mice before and after a 7 d monocular deprivation, which allowed us to examine both the depression component (Dc-ODP) and potentiation component (Pc-ODP) of plasticity independently. We found that CREB, SRF, and MEF2 are all required for ODP, but have differential effects on Dc-ODP and Pc-ODP. CREB is necessary for both Dc-ODP and Pc-ODP, whereas SRF and MEF2 are only needed for Dc-ODP. This finding supports previous reports implicating SRF and MEF2 in long-term depression (required for Dc-ODP), and CREB in long-term potentiation (required for Pc-ODP). Activity-dependent neuronal plasticity is the cellular basis for learning and memory, and it is crucial for the refinement of neuronal circuits during development. Identifying the mechanisms of activity-dependent neuronal plasticity is crucial to finding therapeutic interventions in the myriad of disorders where it is disrupted, such as Fragile X syndrome, Rett syndrome, epilepsy, major depressive disorder, and autism spectrum disorder. Transcription factors are essential nuclear proteins that trigger the expression of gene programs required for long-term functional and structural plasticity changes. Our results elucidate the specific role of the transcription factors CREB, SRF, and MEF2 in the depression and potentiation components of ODP , therefore better informing future attempts to find therapeutic targets for diseases where activity-dependent plasticity is disrupted.
转录因子CREB（环磷酸腺苷反应元件结合因子）、SRF（血清反应因子）和MEF2（肌细胞增强因子2）在神经元可塑性的潜在机制中发挥着关键作用。然而，这些转录因子的激活在可塑性的不同组成部分中所起的作用尚不清楚。在本研究中，我们测试了CREB、SRF和MEF2在眼优势可塑性（ODP）中的作用，ODP是视觉皮层中一种依赖活动的神经元可塑性范式。这三种蛋白质与突触活动反应元件（SARE）结合，SARE是在许多与可塑性相关基因上游发现的一种增强子序列（Kawashima等人，2009年；Rodríguez-Tornos等人，2013年），并且可以协同作用来表达一种ODP所需的基因（McCurry等人，2010年）。我们使用病毒介导的基因转移来阻断视觉皮层中CREB、SRF和MEF2的转录功能，并在7天单眼剥夺前后测量清醒雄性和雌性小鼠的视觉诱发电位，这使我们能够独立检查可塑性的抑制成分（Dc-ODP）和增强成分（Pc-ODP）。我们发现，CREB、SRF和MEF2都是ODP所必需的，但对Dc-ODP和Pc-ODP有不同的影响。CREB对Dc-ODP和Pc-ODP都是必需的，而SRF和MEF2仅对Dc-ODP是必需的。这一发现支持了先前的报道，即SRF和MEF2参与长期抑制（Dc-ODP所必需），而CREB参与长期增强（Pc-ODP所必需）。依赖活动的神经元可塑性是学习和记忆的细胞基础，对发育过程中神经元回路的精细化至关重要。确定依赖活动的神经元可塑性机制对于在众多其被破坏的疾病（如脆性X综合征、雷特综合征、癫痫、重度抑郁症和自闭症谱系障碍）中找到治疗干预措施至关重要。转录因子是必需的核蛋白，可触发长期功能和结构可塑性变化所需的基因程序的表达。我们的结果阐明了转录因子CREB、SRF和MEF2在ODP的抑制和增强成分中的具体作用，因此为未来寻找依赖活动的可塑性被破坏的疾病的治疗靶点提供了更好的信息。
