Role of glial glutamate transporters in V1 plasticity and development

描述（由申请人提供）：视觉皮层中的神经元网络整合突触输入以产生视觉基础的复杂输出。大多数关于视觉皮层功能和发育的研究都集中在神经元上。星形胶质细胞是脑中的非神经元细胞类型，其至少与神经元一样多，并执行多种代谢和支持功能。星形胶质细胞执行几种功能作用，可以影响感觉信息的处理，证据可以在躯体感觉皮层，嗅球和脊髓中找到。在初级视皮层中，定向调节和反应增益调节是视觉的关键特征。这些特征背后的机制涉及兴奋和抑制之间的相互作用，以建立给定神经元的响应特性。我假设星形胶质细胞对这种相互作用有重要贡献。它们的功能之一是在活动期间从突触中移除神经递质。由星形胶质细胞表达的最有影响力的转运体系统之一是谷氨酸转运体系统，其从突触间隙移除突触释放的谷氨酸以缩短传递的时间过程并减少突触外受体或邻近突触的激活。这是一种减少兴奋的机制，在视觉皮层功能中可能很重要。初步证据表明，谷氨酸转运蛋白是维持视觉加工的关键组成部分，因为转运蛋白的抑制会抑制神经反应，并扩大体内视皮层神经元的方向调节。谷氨酸转运蛋白对大脑回路的发育也至关重要，当谷氨酸转运增加或减少时，存在异常皮质发育的证据。谷氨酸转运蛋白的失调与神经发育障碍如精神分裂症和自闭症有关。因此，研究星形胶质细胞的细胞外谷氨酸的调节可以提供有价值的洞察神经网络的发展和功能，通过谷氨酸转运蛋白。 该提案详细介绍了一种实验方法，利用电生理学和最先进的体内成像技术来确定星形胶质细胞谷氨酸转运蛋白在视觉皮层功能和发育中的作用。首先，将使用切片电生理学实验来评估谷氨酸转运体抑制对小鼠初级视觉皮层中的神经元传递的影响。其次，将使用单眼剥夺和星形胶质细胞转运蛋白基因突变小鼠的良好范例研究谷氨酸转运蛋白在皮质发育和经验依赖性可塑性中的作用。最后，在体内成像和电生理学将被用来研究如何抑制谷氨酸转运蛋白的活动改变方向调谐和响应增益的视觉皮层神经元。这些方法的结合将允许星形胶质细胞如何通过谷氨酸转运蛋白调节神经活动和影响视觉皮层的发育和处理的关键评估。

DESCRIPTION (provided by applicant): Neuronal networks in the visual cortex integrate synaptic inputs to make complex outputs that underlie vision. Most studies of visual cortical function and development have focused exclusively on neurons. Astrocytes are a non-neuronal cell type in the brain that are at least as numerous as neurons and perform multiple metabolic and support functions. Astrocytes perform several functional roles that can affect the processing of sensory information, evidence for which can be found in the somatosensory cortex, olfactory bulb, and spinal cord. In the primary visual cortex, orientation tuning and regulation of response gain are critical features of vision. The mechanisms underlying these features involve interplay between excitation and inhibition to establish the response properties of a given neuron. I hypothesize that astrocytes contribute importantly to this interplay. Among their functions is the removal of neurotransmitters from the synapse during activity. One of the most influential transporter systems expressed by astrocytes is the glutamate transporter system, which removes synaptically released glutamate from the synaptic cleft to curtail the time course of transmission and reduce the activation of extrasynaptic receptors or adjacent synapses. This serves as a mechanism to reduce excitation that may be important in visual cortex function. Preliminary evidence suggests that glutamate transporters are a critical component in the maintenance of visual processing, as inhibition of transporters prolongs neural responses and broadens the orientation tuning of visual cortex neurons in vivo. Glutamate transporters are also critical to the development of brain circuits, with evidence existing for abnormal cortical development when there is either increased or decreased glutamate transport. Dysregulation of glutamate transporters has been implicated in neurodevelopmental disorders such as schizophrenia and autism. Therefore, studies into astrocytic regulation of extracellular glutamate could provide valuable insight into neuronal network development and function through glutamate transporters. This proposal details an experimental approach that utilizes electrophysiology and state of the art in vivo imaging techniques to determine the role of astrocyte glutamate transporters in visual cortex function and development. First, the effects of glutamate transporter inhibition on neuronal transmission in primary visual cortex of mice will be assessed using slice electrophysiology experiments. Second, the role of glutamate transporters in cortical development and experience-dependent plasticity will be investigated using the well- established paradigm of monocular deprivation and mice that are mutant for astrocyte transporter genes. Finally, in vivo imaging and electrophysiology will be used to examine how inhibition of glutamate transporter activity alters orientation tuning and response gain of visual cortex neurons. The combination of these methods will allow for a critical assessment of how astrocytes modulate neural activity through glutamate transporters and influence visual cortex development and processing.