Role of mitochondria in GABAergic circuit development

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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.