Synapse-specific effects of synaptically released zinc: implications for auditory processing

项目摘要 大脑的许多区域，包括皮质、海马、基底神经节和边缘结构， 富含突触锌突触锌（以Zn 2+形式）被锌离子加载到突触前囊泡中， 转运蛋白3（ZnT3），在突触传递过程中与谷氨酸共同释放。自从新立科技 锌抑制AMPA和NMDA受体-介导大多数兴奋性多巴胺能神经递质， 突触锌可以调节兴奋性突触信号传导。ZnT3 KO小鼠（ 缺乏突触锌）表现出一系列认知和感觉障碍， 与自闭症和精神分裂症相关的缺陷。越来越多的人类证据表明 某些锌转运蛋白的突变与主要的神经系统疾病有关， 精神分裂症总之，这些发现强烈表明突触锌信号对于 神经元加工这个项目的目标是了解突触锌如何有助于正常的 神经元功能以及锌信号传导中的破坏如何与病理性神经元病症相关联。 我们将采取三种互补的实验方法来解决这些问题。1)使用离体大脑 切片制备和光遗传学刺激范例，我们剖析了突触锌在塑造 皮质微电路中特定突触连接处突触传递的动力学。2)使用 在体内双光子钙成像中，我们评估了突触锌在形成感觉诱发的 在清醒的小鼠中特定类别的听觉皮层神经元的反应。3)使用体外高通量 筛选试验和合理的化合物设计方法，我们正在设计新的工具，以调节 特定锌转运蛋白的功能。这些方法结合起来， 关于突触锌在脑功能中的作用的基本问题，并提供新的机制 深入了解塑造突触和神经处理的内源性机制。

Project Summary Many regions of the brain including the cortex, hippocampus, basal ganglia, and limbic structures are highly enriched with synaptic zinc. Synaptic zinc (as Zn2+) is loaded into presynaptic vesicles by zinc transporter 3 (ZnT3), where it is coreleased with glutamate during synaptic transmission. Since synaptic zinc inhibits AMPA and NMDA receptors – which mediate the majority of excitatory glutamatergic transmission in the brain – synaptic zinc can modulate excitatory synaptic signaling. ZnT3 KO mice (which lack synaptic zinc) display a range of cognitive and sensory impairments and demonstrate behavioral deficits associated with autism and schizophrenia. Mounting evidence from human populations shows that mutations in certain zinc transporters are linked with major neurological disorders such as schizophrenia. Together, these findings strongly suggest that synaptic zinc signaling is important for neuronal processing. The goals of this project are to understand how synaptic zinc contributes to normal neuronal function and how disruptions in zinc signaling are linked to pathological neuronal conditions. We will take three complimentary experimental approaches to these questions. 1) Using ex vivo brain slice preparations and optogenetic stimulation paradigms, we dissect the roles of synaptic zinc in shaping the dynamics of synaptic transmission at specific synaptic connections in cortical microcircuits. 2) Using in vivo 2-photon calcium imaging, we assess the roles of synaptic zinc in shaping the sensory-evoked responses of specific classes of auditory cortical neurons in awake mice. 3) Using in vitro high-throughput screening assays and rational compound design approaches, we are designing novel tools to modulate the function of specific zinc transport proteins. Together these approaches will allow us to answer fundamental questions concerning the role of synaptic zinc in brain function and provide new mechanistic insights into endogenous mechanisms that shape synaptic and neural processing.