Accumulating evidence suggests that global depletion of adult hippocampal neurogenesis influences its function and the timing of the depletion impacts the deficits. However, behavioral roles of adult-born neurons during their establishment of projections to CA3 pyramidal neurons remain largely unknown. Here we combined retroviral and optogenetic approaches to birth-date and reversibly control a group of adult-born neurons in adult mice. We show that adult-born neurons form functional synapses on CA3 pyramidal neurons as early as 2 weeks after birth, and that this projection to the CA3 area becomes stable by 4 weeks in age. Newborn neurons at this age exhibit enhanced plasticity compared to other stages. Notably, we found that reversibly silencing this cohort of ~4 week-old cells after training, but not cells of other ages, substantially disrupted retrieval of hippocampal memory. Our results identify a restricted time window for adult-born neurons exhibiting an essential role in hippocampal memory retrieval.

New neurons are continuously generated in the subgranular zone of the adult hippocampus and, once sufficiently mature, are thought to integrate into hippocampal memory circuits. However, whether they play an essential role in subsequent memory expression is not known. Previous studies have shown that suppression of adult neurogenesis often (but not always) impairs subsequent hippocampusdependent learning (i.e., produces anterograde effects). A major challenge for these studies is that these new neurons represent only a small subpopulation of all dentate granule cells, and so there is large potential for either partial or complete compensation by granule cells generated earlier on during development. A potentially more powerful approach to investigate this question would be to ablate adultgenerated neurons after they have already become part of a memory trace (i.e., retrograde effects). Here we developed a diphtheria toxin-based strategy in mice that allowed us to selectively ablate a population of predominantly mature, adult-generated neurons either before or after learning, without affecting ongoing neurogenesis. Removal of these neurons before learning did not prevent the formation of new contextual fear or water maze memories. In contrast, removal of an equivalent population after learning degraded existing contextual fear and water maze memories, without affecting nonhippocampal memory. Ablation of these adult-generated neurons even 1 month after learning produced equivalent memory degradation in the water maze. These retrograde effects suggest that adultgenerated neurons form a critical and enduring component of hippocampal memory traces.

A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network.