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Newborn dentate granule cells (DGCs) are generated in the hippocampal dentate gyrus (DG) of rodents through a process called adult hippocampal neurogenesis, which is subjected to tight intrinsic and extrinsic regulation. The use of retroviruses encoding fluorescent proteins has allowed the characterization of the maturation dynamics of newborn DGCs, including their morphological development and the establishment and maturation of their afferent and efferent synaptic connections. However, the study of a crucial cellular compartment of these cells, namely, the axon initial segment (AIS), has remained unexplored to date. The AIS is not only the site of action potential initiation, but it also has a unique molecular identity that makes it one of the master regulators of neural plasticity and excitability. Here we examined the dynamics of AIS formation in newborn DGCs of young female adult C57BL/6J mice in vivo. Our data reveal notable changes in AIS length and thickness throughout cell maturation under physiological conditions and show that the most remarkable structural changes coincide with periods of intense morphological and functional remodeling. Moreover, we demonstrate that AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from Escherichia coli) stimuli. [ABSTRACT FROM AUTHOR]