Mechanisms of Presynaptic Plasticity in Visual Cortex

描述（由申请人提供）：视觉皮层神经元的反应可以经历经验依赖的变化，特别是在生命早期。在这个“关键时期”的不正常经历可能会永久性地损害视力（如弱视），这是由于大脑皮层连接不当造成的。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（NMDARs）的激活是许多形式的经验依赖可塑性所必需的。虽然传统上认为NMDARs在突触后发挥作用，但最近的一项令人惊讶的发现是NMDARs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释放和突触强度的长期抑制（LTD）。在动物发育过程中，突触前和突触后NMDARs的相对作用尚不清楚，但这一信息对于理解关键时期突触传递和可塑性的基本机制是如何变化的至关重要。我们的数据首次证明，突触前NMDAR功能的突然丧失与视觉皮质可塑性的关键时期的开始一致。在这里，我们将检验突触前NMDARs在关键时期开始前参与LTD诱导的中心假设，但它们的经验依赖性损失触发了新的LTD诱导机制的出现。我们将在小鼠身上使用电生理和解剖学方法来解决三个关键问题。(1)是什么让突触前NMDARs发挥作用，是什么导致了它们的发育丧失？(2)经验是否改变了年龄依赖性水手突触前NMDARs的功能？(3)突触前NMDARs如何促进突触传递和可塑性？由于兴奋性突触的受限是视觉反应性可能因异常视觉经验而丧失的机制之一，因此一个特别重要的目标是阐明突触前NMDARs在受限中的参与以及在关键时期这可能有何不同。通过证明突触前和突触后NMDARs都有助于突触可塑性的表达，并且它们的相对作用在发育过程中发生变化，我们的研究结果有望定义新兴皮层回路中突触可塑性的一种新颖的，也许是普遍的特性。与公共卫生的相关性：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预防视觉剥夺的有害后果的合理策略，并将增加我们对正常视觉皮层发育的理解。

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.