Development of adult-generated cell connectivity with excitatory and inhibitory cell populations in the hippocampus

Abstract

New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Although the addition of these new neurons may facilitate the formation of new memories, as they integrate, they provide additional excitatory drive to CA3 pyramidal neurons. During development, to maintain homeostasis, new neurons form preferential contacts with local inhibitory circuits. Using retroviral and transgenic approaches to label adult-generated granule cells, we first asked whether a comparable process occurs in the adult hippocampus in mice. Similar to development, we found that, during adulthood, new neurons form connections with inhibitory cells in the dentate gyrus, hilus, and CA3 regions as they integrate into hippocampal circuits. In particular, en passant bouton and filopodia connections with CA3 interneurons peak when adult-generated dentate granule cells (DGCs) are~4 weeks of age, a time point when these cells are most excitable. Consistent with this, optical stimulation of 4-week-old (but not 6- or 8-week-old) adult-generated DGCs strongly activated CA3 interneurons. Finally, we found that CA3 interneurons were activated robustly during learning and that their activity was strongly coupled with activity of 4-week-old (but not older) adult-generated DGCs. These data indicate that, as adult-generated neurons integrate into hippocampal circuits, they transiently form strong anatomical, effective, and functional connections with local inhibitory circuits in CA3.