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

大脑的一个基本特性是它具有高度的可塑性，这意味着它能够根据感官输入、学习、社会和身体互动、接触药物和激素或受伤所提供的体验而改变和适应。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所介导的。可塑性可以包括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，或细胞或突触的损失。哺乳动物的大脑皮层在可塑性方面具有重要意义，因为它执行了许多最高级别的心理功能。我们的目标是通过动物模型来推进我们对哺乳动物大脑皮层中负责调节经验依赖可塑性的细胞、分子和行为机制的理解。具体地说，我们使用了体感系统通路，在那里我们可以很容易地在体感皮层的水平上操纵感觉体验。我们可以通过被动刺激须状物来驱动特定的活动模式，或者我们可以通过修剪或拔掉须状物来剥夺皮层的感官输入。在这个建议中，我们特别感兴趣的是理解大脑皮层中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/神经调节剂。我们称这些神经元为锌能神经元，因为它们以活性和钙依赖的方式将锌隔离到突触囊泡中，并将锌释放到突触间隙中。我们已经证明，锌的水平在大脑皮层神经元显著增加后，感觉剥夺。我们的首要假设是，感觉剥夺引起的突触锌水平的增加促进了突触抑制和突触减弱。长时间的剥夺可能导致突触重塑和/或消除。正是通过这种方式，我们认为锌介导了突触的可塑性。我们将使用两种缺乏锌突触信号所必需的关键蛋白质的突变小鼠来验证我们的假设。ZnT3基因敲除小鼠缺乏一种负责将锌包装到神经元突触囊泡中的蛋白质，因此不具备利用锌发出信号的能力。GPR39基因敲除小鼠缺乏一种重要的结合锌的受体，因此，这是转导释放的锌传递的信号所必需的。我们将通过去除须来诱导这些小鼠的皮质可塑性，并使用最先进的生理、细胞、分子和行为方法将它们与正常小鼠进行比较。**

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. **