Role of mitochondria in GABAergic circuit development

gaba能神经元是大脑神经元群中一个重要的子集，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的增殖、分化和连接等过程来强烈调节大脑发育。到目前为止，脑回路的复杂性和gaba能细胞群的非同质性使得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作gaba能中间神经元特定子集的技术。gaba能神经元的主要群体是篮细胞，它们与目标神经元的体细胞和近端树突形成强烈的抑制性连接。篮状细胞突触如此精确的亚细胞定位，再加上它们以惊人的高频率持续发射短动作电位的惊人能力，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。如此高频率活动的能量需求表明，线粒体在篮细胞突触传递中发挥着重要作用。事实上，最近的许多研究表明，线粒体的运输和定位对兴奋性突触的功能和可能的可塑性至关重要，但它们在gaba能突触发育中的作用尚不清楚。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gaba能突触成熟中的作用。我们的中心假设是，线粒体在突触前末端的活性依赖定位对于细胞周围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.