Role of mitochondria in GABAergic circuit development

GABA能神经元是大脑中神经元群体的一个重要子集，它有力地控制着大脑回路的功能。此外，它们还通过调节神经元增殖、分化和连接等几个过程来强烈调控大脑发育。到目前为止，大脑电路的复杂性和GABA能细胞群的非均质性使得研究这些神经元如何发育和形成突触连接变得非常困难。我们最近开发了标记和操纵GABA能中间神经元的特定子集的技术。GABA能神经元的优势群是篮状细胞，它们与靶神经元的胞体和近端的树突形成强烈的抑制性联系。篮子细胞突触的这种精确的亚细胞定位，加上它们以极高的频率发射持续的短暂动作电位序列的打击能力，使它们能够有力地控制目标细胞的输出，并影响大脑中的大型网络活动。如此高频率的活动对能量的需求表明，线粒体在篮子细胞中对突触传递的正常功能起着重要作用。事实上，最近的许多研究表明，线粒体的运输和定位对于兴奋性突触功能和可能的可塑性是必不可少的，但它们在GABA能突触发育中的作用尚不清楚。利用尖端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，突触前末端线粒体的活性依赖的定位对于体周GABA能突触的正确成熟是必不可少的。

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.