Optical controlling reveals time- dependent roles for adult-born dentate granule cells Yan Gu, Maithe Arruda-Carvalho, Jia Wang, Stephen R Janoschka, Sheena A Josselyn ， Paul W Frankland & Shaoyu Ge 1

Background The adult hippocampus continues to give rise to several thousand new dentate granule cells everyday. Studies using global perturbation or ablation of adult hippocampal neurogenesis has revealed deficits in some forms of hippocampal memory.. 2

As the morphological and physiological phenotypes of adult-born cells change markedly as they mature, they may have distinct roles at different stages following integration into hippocampal circuits. Adult-born dentate granule cells (DGCs) extend dendrites receive functional input from the existing neural circuits as early as 2 weeks after birth. Input (dendritic) synapses of adult-born neurons show enhanced plasticity between 4–6 weeks after birth compared with other stages. Background 3

What is the precise timing for these adult-born functional output synapse formation and maturation? Whether do output synapses, if formed and functional, also exhibit heightened plasticity around the same time? What is its functional role? Questions 4

Methods Optogenetic stimulation Water maze Classical fear conditioning Retroviral birth-dating + Gene delivery (EGFP+ Light gated ion channels) Electrophysiological experiments Behavioral experiments Synaptic transmission efficiency, Capability of LTP 5

Results Birth-dating and labeling newborn DGCs Experimental timeline Labeling specificity of newborn DGCs with high-titer retrovirus No mature DGC-like cells at 1 and 2 wpi 6

Results Adult-born DGCs fully integrate into the hippocampal trisynaptic circuits by ~4 wpi Adult-born neurons form functional synapses on CA3 pyramidal neurons 7

Results Heightened synaptic plasticity of young adult-born neurons 8

Results Output synapses of mature newborn DGCs remain plastic, but have a higher induction threshold Young newborn neurons exhibit heightened plasticity that peaks at ~4 wpi 9

Conclusion 1 Adult-born DGCs fully incorporate into the hippocampal trisynaptic neural circuit around 4 wpi and DGCs at this age have more excitable membranes and enhanced input/output synaptic plasticity. 10

Results Optical silencing of newborn DGCs does not influence acquisition of spatial memory 11

Results Silencing young newborn neurons affects spatial memory retrieval labeled ~4-week-old adult-born DGCs regulate spatial memory retrieval. 12

Results Silencing young newborn neurons impairs retrival of contextural fear memory 13

Results The behavioral role for newborn DGCs relies on their age 14

Results Heightened plasticity in young newborn neurons may be important for memory retrieval 15

Results Silencing newborn neurons at 4 wpi, but not 8 wpi, disrupted memory retrieval in both tasks 16

Conclusion 2 Adult-born neurons may be transiently critical for memory retrieval, but the effect, at least in spatial and contextual memory retrieval, may decline as these adult-born neurons continue to mature. 17

Thank you 18