The role of zincergic neurons, and zinc signalling, in cortical plasticity

锌能神经元和锌信号传导在皮质可塑性中的作用

• 批准号: RGPIN-2015-05650
• 负责人: Dyck, Richard
• 金额: $ 2.91万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613671
• 关键词: role; zincergic; neurons; zinc; signalling

A fundamental property of the brain is that it is highly plastic, meaning that it is capable of changing and adapting as a result of experiences provided by sensory inputs, learning, social and physical interactions, exposure to drugs and hormones, or injury. This plasticity is mediated by changes to the structure and function of neural cells at molecular, cellular, synaptic and network levels. Plasticity can involve the experience-dependent strengthening of synaptic connections, or the formation of new cells or synapses. As importantly, plasticity can involve the experience-dependent weakening of synaptic connections, or the loss of cells or synapses. The mammalian cerebral cortex is of key interest with regard to plasticity because it carries out many of the highest levels of mental functioning. Our goal is to advance our understanding of the cellular, molecular and behavioural mechanisms responsible for mediating experience-dependent plasticity in the mammalian cerebral cortex using an animal model. Specifically, we use the whisker somatosensory system pathway, where we can easily manipulate sensory experience at the level of the somatosensory cortex. We can drive specific patterns of activity by passively stimulating a whisker, or we can deprive the cortex of sensory input by trimming or plucking the whisker. In this proposal, we are particularly interested in understanding the contribution, to synaptic plasticity, of a discrete population of neurons within the cerebral cortex, those that release zinc as a neurotransmitter/neuromodulator. We refer to these neurons as zincergic because they sequester zinc into synaptic vesicles and release zinc into the synaptic cleft in an activity- and calcium-dependent manner. We have shown that the levels of zinc in cerebral cortical neurons increases significantly following sensory deprivation. Our overarching hypothesis is that sensory deprivation-induced increases in the levels of synaptic zinc promote synaptic inhibition and synaptic weakening. With prolonged periods of deprivation this could lead to synaptic remodelling and/or elimination. It is in this way that we think that zinc mediates synaptic plasticity. We will test our hypothesis using two strains of mutant mice that lack critical proteins necessary for synaptic signalling by zinc. The ZnT3 knockout mice lack the one protein responsible for packaging zinc into synaptic vesicles of neurons and do not, therefore, have the ability to signal using zinc. The GPR39 knockout mice lack an important receptor that binds zinc and is, therefore, necessary to transduce the signal conveyed by released zinc. We will examine these mice after inducing cortical plasticity by whisker removal, and compare them to normal mice, using state-of-the-art physiological, cellular, molecular and behavioural methods.

大脑的一个基本特性是它具有高度的可塑性，这意味着它能够随着感官输入、学习、社会和身体互动、接触药物和激素或受伤所提供的经验而改变和适应。这种可塑性是由神经细胞在分子、细胞、突触和网络水平上的结构和功能变化介导的。可塑性可以涉及突触连接的经验依赖性加强，或新细胞或突触的形成。同样重要的是，可塑性可能涉及突触连接的经验依赖性减弱，或者细胞或突触的丧失。哺乳动物的大脑皮层在可塑性方面具有关键意义，因为它执行许多最高水平的心理功能。我们的目标是推进我们的理解的细胞，分子和行为机制负责调解经验依赖可塑性的哺乳动物大脑皮层使用动物模型。具体来说，我们使用触须体感系统通路，在那里我们可以很容易地操纵体感皮层水平的感觉经验。我们可以通过被动地刺激胡须来驱动特定的活动模式，或者我们可以通过修剪或拔胡须来剥夺皮层的感觉输入。 在这个提议中，我们特别感兴趣的是了解大脑皮层内离散的神经元群体对突触可塑性的贡献，这些神经元释放锌作为神经递质/神经调质。我们称这些神经元为锌能神经元，因为它们将锌隔离到突触囊泡中，并以活性和钙依赖性方式将锌释放到突触间隙中。我们已经表明，大脑皮层神经元中的锌水平增加显着感觉剥夺。我们的总体假设是，感觉剥夺诱导的突触锌水平的增加促进突触抑制和突触减弱。随着剥夺时间的延长，这可能导致突触重塑和/或消除。正是通过这种方式，我们认为锌介导突触可塑性。我们将使用两种突变小鼠来测试我们的假设，这些小鼠缺乏锌突触信号传导所必需的关键蛋白质。ZnT 3敲除小鼠缺乏负责将锌包装到神经元突触囊泡中的一种蛋白质，因此不具有使用锌发出信号的能力。GPR 39基因敲除小鼠缺乏一种重要的结合锌的受体，因此，它是抑制释放的锌所传递的信号所必需的。我们将使用最先进的生理学、细胞学、分子学和行为学方法，在通过去除胡须诱导皮质可塑性后检查这些小鼠，并将它们与正常小鼠进行比较。