Experience Dependent Plasticity in a fosGFP Mouse

描述（由申请人提供）：控制突触元可塑性（可塑性的可塑性）的规则在发育中的神经系统中具有特别重要的意义，其中经验在神经反应的模式中具有重要作用，并且先前的突触活动对未来突触变化的影响可能具有深远的后果。我们已经开发并采用了fosGFP转基因小鼠来鉴定体感觉新皮层中经验依赖变化的位点。在对照动物中，nmdar依赖性LTP可以在体外4-2/3层突触产生，正常经验导致这些突触在出生后第二和第三周逐渐加强。须刺激增强突触强度，并导致可塑性基础的分子机制发生转变，从nmdar依赖性增强到mglur依赖性增强。本研究旨在通过体内和体外分析，确定谷氨酸受体特定亚型的激活如何启动和维持累积的、经验依赖的可塑性。公共卫生相关性：学习经常发生在重复的刺激呈现中，并随着时间的推移而累积，特别是在新皮层中。这种累积突触变化的细胞和分子基础需要对正在经历持续修改的特定突触进行识别和分析。利用转基因fosGFP小鼠定位可塑性发生的新皮层的精确区域，我们可以确定经验依赖可塑性的突触底物，并确定在这种学习形式中调用的分子机制。我们发现，在感觉皮层的经验依赖性可塑性开始后，nmdar依赖性可塑性的方向被逆转，随后的突触强化需要mGluRs的激活。经验改变谷氨酸受体亚型的功能和定位的分子机制对学习和记忆的研究至关重要。

DESCRIPTION (provided by applicant): The rules governing synaptic metaplasticity (the plasticity of plasticity) are of special importance in the developing nervous system, where experience has an important role in the patterning of neural responses and the influence of prior synaptic activity on future synaptic change can have profound consequences. We have developed and employed a fosGFP transgenic mouse to identify the locus of experience-dependent change in somatosensory neocortex. In control animals, NMDAR-dependent LTP can be generated at layer 4-2/3 synapses in vitro, and normal experience results in the progressive strengthening of these synapses over the second and third postnatal week. Whisker stimulation enhances synaptic strength and leads to a transformation in the molecular mechanisms that underlie plasticity, from NMDAR-dependent to mGluR-dependent potentiation. This proposal seeks to identify how cumulative, experience-dependent plasticity is initiated and maintained by the activation by specific subtypes of glutamate receptors, using both in vivo and in vitro analysis. PUBLIC HEALTH RELEVANCE: Learning frequently takes place over repeated stimulus presentations and is cumulative over time, especially in the neocortex. The cellular and molecular basis for this type of cumulative synaptic change requires identification and analysis of the specific synapses that are undergoing continuous modifications. Using a fosGFP transgenic mice to locate the precise area of the neocortex where plasticity is occurring, we can identify the synaptic substrates of experience-dependent plasticity and determine the molecular mechanisms that are invoked during this form of learning. We have found that the direction of NMDAR-dependent plasticity is reversed after the onset of experience-dependent plasticity in sensory neocortex, and that subsequent synaptic strengthening requires activation of mGluRs. The molecular mechanisms by which experience alters the function and localization of glutamate receptor subtypes is of essential interest to studies of learning and memory.