Role of mitochondria in GABAergic circuit development

GABA能神经元是脑内神经元的重要组成部分，对脑回路的功能起着重要的控制作用。此外，它们通过调节几个过程如神经元增殖、分化和连接来强烈调节脑发育。大脑回路的复杂性和GABA能细胞群的非同质性使得迄今为止对这些神经元如何发育和形成突触连接的研究非常困难。我们最近开发了标记和操纵特定亚群的GABA能中间神经元的技术。主要的GABA能神经元群是篮状细胞，其在其靶神经元的索马和近端树突上形成强抑制性连接。篮状细胞突触的这种精确的亚细胞定位，加上它们以非常高的频率发射持续的短暂动作电位序列的惊人能力，使它们能够有力地控制其靶细胞的输出，并影响大脑中的大型网络活动。这种高频率活动的能量需求表明，线粒体在篮状细胞中对突触传递的正常功能起着重要作用。事实上，许多最近的研究表明，线粒体的运输和定位是必不可少的兴奋性突触功能和可能的可塑性，但他们的作用在GABA能突触发育是未知的。利用先进的实时成像和基因操作技术，我们建议研究线粒体在发育中的大脑中GABA能突触成熟中的作用。我们的中心假设是，活动依赖性定位的线粒体在突触前末梢是必不可少的正确成熟的体周GABA能突触。

GABAergic neurons form an important subset of the neuronal population in the brain, which powerfully control the function of brain circuits. In addition, they strongly regulate brain development by modulating several processes such as neuronal proliferation, differentiation and connectivity. The complexity of brain circuitry and the non-homogeneity of the GABAergic cell population has so far made the study of how these neurons develop and form synaptic connections, very difficult. We have recently developed techniques to label and manipulate specific subset of GABAergic interneurons. The predominant group of GABAergic neurons are basket cells which form strong inhibitory connections onto the soma and proximal dendrite of their target neurons. Such precise subcellular location of basket cell synapses in conjunction with their striking ability to fire sustained trains of brief action potentials at remarkably high frequency, allows them to powerfully control the output of their target cells and influence large network activities in the brain. The energy demands of such a high frequency activity suggests an important role of mitochondria for synaptic transmission to function normally in basket cells. Indeed, many recent studies show that mitochondrial transport and localization are essential for excitatory synaptic function and likely plasticity, however their role during GABAergic synapse development is unknown. Using cutting-edge live imaging and gene manipulation techniques, we propose to investigate the role of mitochondria in the maturation of GABAergic synapses in the developing brain. Our central hypothesis is that activity-dependent localization of mitochondria at the presynaptic terminals is essential for the correct maturation of perisomatic GABAergic synapses.