Mechanisms of Presynaptic Plasticity in Visual Cortex

描述(申请人提供)：视皮层神经元的反应可以经历经验依赖的变化，特别是在生命的早期。在这一“关键时期”的异常经历可能会由于皮质连接不当而永久性损害视力(例如弱视)。这证明了经验依赖性突触可塑性的重要性。NMDA型谷氨酸受体(NMDAR)的激活是许多形式的经验依赖性可塑性所必需的。虽然传统上认为NMDAR在突触后发挥其影响，但最近一个令人惊讶的发现是，NMDAR在发育早期也在突触前表达。这些突触前受体参与调节神经递质的释放和突触强度的长期抑制(LTD)。突触前和突触后NMDAR在动物发育过程中的相对贡献尚不清楚，但这一信息对于理解突触传递和可塑性的基本机制在关键期开始时如何变化至关重要。我们的数据首次显示了突触前NMDAR功能的突然丧失，这与视觉皮质可塑性关键期的开始相吻合。在这里，我们将检验这一中心假设，即突触前NMDAR在关键期开始之前参与LTD的诱导，但它们的经验依赖性丢失触发了新的LTD诱导机制的出现。我们将在小鼠身上使用电生理学和解剖学方法来解决三个关键问题。(1)是什么允许突触前NMDAR发挥作用，是什么导致它们的发育丧失？(2)经验是否改变了年龄相关水手中突触前NMDAR的功能？(3)突触前NMDAR如何促进突触传递和可塑性？由于兴奋性突触的LTD是视觉体验异常导致视觉反应丧失的一种机制，一个特别重要的目标是阐明突触前NMDAR在LTD中的参与及其在关键时期的变化。通过证明突触前和突触后的NMDAR都有助于突触可塑性的表达，以及它们在发育过程中的相对作用发生变化，我们的发现有望定义新出现的皮质环路中突触可塑性的一种新的、甚至是一般的特性。与公共卫生相关：弱视是儿童时期最常见的视力损害形式，如果不加以治疗，将是永久性的。被剥夺的眼睛驱动的突触输入的减弱被认为是视觉缺陷的基础。因此，了解突触减弱的基本机制将导致制定合理的策略来预防视觉剥夺的有害后果，并将增加我们对正常视觉皮质发育的理解。

DESCRIPTION (provided by applicant): The responses of neurons in the visual cortex can undergo experience-dependent changes, particularly during early life. Abnormal experience during this "critical period" can permanently impair vision (e.g. amblyopia) due to improper cortical wiring. This demonstrates the importance of experience-dependent synaptic plasticity. Activation of NMDA-type glutamate receptors (NMDARs) is required for many forms of experience-dependent plasticity. While NMDARs are traditionally thought to exert their influences postsynaptically, a surprising recent finding is that NMDARs are also expressed presynaptically early in development. These presynaptic receptors are involved in regulating neurotransmitter release and long-term depression (LTD) of synaptic strength. The relative contribution of pre- and postsynaptic NMDARs during animal development remains unknown, yet this information is crucial to understanding how fundamental mechanisms of synaptic transmission and plasticity change at the onset of the critical period. Our data demonstrate, for the first time, an abrupt loss of presynaptic NMDAR function that coincides with the onset of the critical period for visual cortical plasticity. Here we will examine the central hypothesis that presynaptic NMDARs are involved in the induction of LTD before the onset of the critical period, but their experience- dependent loss triggers a new LTD induction mechanism to emerge. We will use electrophysiological and anatomical approaches in mice to address three crucial questions. (1) What allows presynaptic NMDARs to function, and what underlies their developmental loss? (2) Does experience modify the function of presynaptic NMDARs in an age-dependent mariner? (3) How do presynaptic NMDARs contribute to synaptic transmission and plasticity? Because LTD of excitatory synapses is one mechanism by which visual responsiveness may be lost due to aberrant visual experience, a particularly important goal is to elucidate the involvement of presynaptic NMDARs in LTD and how this might differ during the critical period. By demonstrating that both pre- and postsynaptic NMDARs contribute to the expression of synaptic plasticity, and that their relative roles shift over development, our findings are expected to define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits. Relevance to public health: Amblyopia is the most common form of visual impairment during childhood and, if left untreated, is permanent. The weakening of synaptic inputs driven by the deprived eye is thought to underlie the visual deficits. Accordingly, knowledge of the fundamental mechanisms of synaptic weakening will lead to rational strategies for preventing the deleterious consequences of visual deprivation and will increase our understanding of normal visual cortical development.