title: 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. Significance statement: New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Understanding how these cells integrate within well formed circuits will increase our knowledge about the basic principles governing circuit assembly in the adult hippocampus. This study uses a combined connectivity analysis (anatomical, functional, and effective) of the output connections of adult-born hippocampal cells to show that, as these cells integrate into hippocampal circuits, they transiently form strong connections with local inhibitory circuits. This transient increase of connectivity may represent an homeostatic process necessary to accommodate changes in the excitation/inhibition balance induced by the addition of these new excitatory cells to the preexisting excitatory hippocampal circuits.
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada, M5G 0A4, and.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Restivo
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada, M5G 0A4, and.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Niibori
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada, M5G 0A4, and.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mercaldo
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada, M5G 0A4, and Departments of Psychology and Physiology and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada, M5G 0A4, and Departments of Psychology and Physiology and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada, M5S 1A8 paul.frankland@sickkids.ca.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology; D000375:Aging; D000818:Animals; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D062308:Optogenetics
keywords: CA3; adult neurogenesis; dentate gyrus; mossy fibers; optogenetics