SUMMARY Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (four-week-old) GCs can efficiently drive distal CA3 targets, but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition towards maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus.

The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturation when their intrinsic electrical activity was reduced by the cell-autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus.

SUMMARY Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.