Rapid integration of young newborn dentate gyrus granule cells in the adult hippocampal circuitry

Abstract

Newborn dentate gyrus granule cells (DGCs) are integrated into the hippocampal circuitry and contribute to the cognitive functions of learning and memory. The dendritic maturation of newborn DGCs in adult mice occurs by the first 3-4 weeks, but DGCs seem to receive a variety of neural inputs at both their dendrites and soma even shortly after their birth. However, few studies on the axonal maturation of newborn DGCs have focused on synaptic structure. Here, we investigated the potentiality of output and input in newborn DGCs, especially in the early period after terminal mitosis. We labeled nestin-positive progenitor cells by injecting GFP Cre-reporter adenovirus into Nestin-Cre mice, enabling us to trace the development of progenitor cells by their GFP expression. In addition to GABAergic input from interneurons, we observed that the young DGCs received axosomatic input from the medial septum as early as postinfection day 7 (PID 7). To evaluate the axonal maturation of the newborn DGCs compared with mature DCGs, we performed confocal and electron microscopic analyses. We observed that newborn DGCs projected their mossy fibers to the CA3 region, forming small terminals on hilar or CA3 interneurons and large boutons on CA3 pyramidal cells. These terminals expressed vesicular glutamate transporter 1, indicating they were glutamatergic terminals. Intriguingly, the terminals at PID 7 had already formed asymmetric synapses, similar to those of mature DGCs. Together, our findings suggest that newborn DGCs may form excitatory synapses on both interneurons and CA3 pyramidal cells within 7 days of their terminal mitosis.

Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

“…5) lags behind the study of their dendritic maturation and, in particular, its regulation by extrinsic factors has not been investigated. In standard-housed mice, by 1-wk postmitosis there is significant axonal invasion of CA3 Faulkner et al 2008;Ide et al 2008). However, electron microscopy studies addressing when these axons generate functional synapses have generated somewhat discordant results.…”

“…However, electron microscopy studies addressing when these axons generate functional synapses have generated somewhat discordant results. Ide et al (2008) observed that 1-wk post-mitosis MF boutons expressed vGlut1 and on occasion formed rudimentary synapses on dendritic shafts, whereas 2-wk-old MFs formed complex synapses that differed little from mature ones. Faulkner et al (2008), however, found that 2-wk-old terminals are immature and only become relatively complex at 4 wk, with continued maturation over the next 3 mo.…”

“…Ide et al (2008) showed that smaller synapses considerably outnumbered large boutons in both the hilus and CA3, with potentially a small overexuberance at 2 wk of age that decreased by 9-wk postmitosis. (Although this analysis assumed that small synapses were specific IN targeting synapses and not an early developmental stage of large mossy terminals.…”

Development of Adult-Generated Cell Connectivity with Excitatory and Inhibitory Cell Populations in the Hippocampus

“…The vast majority of these cells differentiate into neurons and migrate into the granule cell layer of the dentate gyrus (DG). They extend dendritic processes toward the molecular layer of the DG and mossy fiber axons toward targets in the hilus and CA3 region, eventually forming input and output synaptic connections Toni et al, 2007Toni et al, , 2008Faulkner et al, 2008;Ide et al, 2008;Tronel et al, 2010;Deshpande et al, 2013;Sun et al, 2013). Although this sequence is invariable, integration of newly generated neurons into hippocampal circuits proceeds at a slower rate during adulthood than during development (Duan et al, 2008).…”

Perspectivas de terapia celular em neurologia

“…Os neurônios da ZSV tendem a migrar majoritariamente para o bulbo olfatório, integrandose aos circuitos locais que compõem a memória olfativa 9 . Já as células do DG tendem a originar neurônios granulares, que se integram a circuitos hipocampais relacionados à memória declarativa 10 . Nessas duas regiões, há um tipo especializado de astrócito em formato estrelado (positivo para GFAP e nestina), que pode ser considerado a verdadeira célula-tronco neural fisiológica.…”