Neuronal Differentiation in the Adult Hippocampus Recapitulates Embryonic Development

New neurons, which have been implicated in pattern separation, are continually generated in the dentate gyrus in the adult hippocampus. Using a genetically modified rabies virus, we demonstrated that molecular layer perforant pathway (MOPP) cells innervated newborn granule neurons in adult mouse brain. Stimulating the perforant pathway resulted in the activation of MOPP cells before the activation of dentate granule neurons. Moreover, activation of MOPP cells by focal uncaging of glutamate induced strong inhibition of granule cells. Together, these results indicate that MOPP cells located in the molecular layer of the dentate gyrus contribute to feed-forward inhibition of granule cells via perforant pathway activation.adult neurogenesis | interneuron

Section: Resultssupporting

confidence: 86%

Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus

Li¹,

Stam²,

Aimone³

et al. 2013

“…Although the existence of synaptic inputs to the dendrites of adultborn neurons has been well documented (5)(6)(7)(8)(9)(10)(11)(12), there is a lack of knowledge regarding whether and when the axons of new neurons form synaptic outputs. This makes the claim of their full integration into existing neural circuitry premature.…”

mentioning

confidence: 99%

Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain

Faulkner

Jang

Liu

et al. 2008

193

179

New neurons are continuously generated in restricted regions of the adult mammalian brain. Although these adult-born neurons have been shown to receive synaptic inputs, little is known about their synaptic outputs. Using retrovirus-mediated birth-dating and labeling in combination with serial section electron microscopic reconstruction, we report that mossy fiber en passant boutons of adult-born dentate granule cells form initial synaptic contacts with CA3 pyramidal cells within 2 weeks after their birth and reach morphologic maturity within 8 weeks in the adult hippocampus. Knockdown of Disrupted-in-Schizophrenia-1 (DISC1) in newborn granule cells leads to defects in axonal targeting and development of synaptic outputs in the adult brain. Together with previous reports of synaptic inputs, these results demonstrate that adultborn neurons are fully integrated into the existing neuronal circuitry. Our results also indicate a role for DISC1 in presynaptic development and may have implications for the etiology of schizophrenia and related mental disorders.adult neurogenesis ͉ synaptogenesis ͉ DISC1 ͉ hippocampus ͉ axon guidance N ew neurons generated in the adult mammalian brain are believed to contribute to specific brain functions (1-4). Although the existence of synaptic inputs to the dendrites of adultborn neurons has been well documented (5-12), there is a lack of knowledge regarding whether and when the axons of new neurons form synaptic outputs. This makes the claim of their full integration into existing neural circuitry premature. Newborn dentate granule cells (DGCs) in the adult hippocampus are known to extend their axons into the CA3 subfield (8,13,14), but it is unclear whether typical synaptic structures are formed by these new neurons in vivo. Using a retrovirus expressing EGFP to birth-date and label adultborn neurons (5,8,15), we examined the development of their axons and synaptic outputs by confocal and quantitative immunoelectron microscopy (EM) with 3D reconstruction of labeled boutons (15-17). We show that the axons of adult-born DGCs form typical mossy fiber bouton synaptic complexes with CA3 pyramidal cells within 8 weeks.To explore the molecular mechanisms regulating axonal outputs by new neurons in the adult brain, we examined the role of disc1, a susceptibility gene for schizophrenia and other major mental illness (18)(19)(20). DISC1 (Disrupted-in-Schizophrenia-1) is highly expressed in the developing and adult hippocampus (21), and its expression pattern, together with the recent identification of a large number of DISC1 interacting proteins (22), strongly suggests potential roles for DISC1 in regulating neuronal development (18)(19)(20). The in vivo cellular functions of DISC1, however, are not completely understood. Interfering with DISC1 function in utero leads to defects in embryonic cortical neuronal migration and dendritic orientation (23). Perturbation of DISC1 functions in genetically modified mice by deleting a subset of DISC1 isoforms leads to some defects in migration and dendri...

“…At this age, adult-generated cells are not fully mature. They extend axons to CA3 and apical dendrites into the molecular layer of the DG and initiate their synaptic integration (8,11,(30)(31)(32)(33). At the functional level, 1-to 2-week-old neurons are highly excitable (29,34).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory

Trouche

Bontempi

Roullet

et al. 2009

170

135

The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult mammalian brain that become functionally integrated into existing neural circuits. To what extent this form of plasticity contributes to memory functions remains to be elucidated. Using mapping of activity-dependent gene expression, we visualized in mice injected with the birthdating marker 5-bromo-2 -deoxyuridine the recruitment of new neurons in a set of controlled water maze procedures that engage specific spatial memory processes and require hippocampal-cortical networks. Here, we provide new evidence that adult-generated hippocampal neurons make a specific but differential contribution to the processing of remote spatial memories. First, we show that new neurons in the DG are recruited into neuronal networks that support retrieval of remote spatial memory and that their activation is situation-specific. We further reveal that once selected, new hippocampal neurons are durably incorporated into memory circuits, and also that their recruitment into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. We find that initial spatial training during a critical period, when new neurons are more receptive to surrounding neuronal activity, favors their subsequent recruitment upon remote memory retrieval. We therefore hypothesize that new neurons activated during this critical period become tagged so that once mature, they are preferentially recruited into hippocampal networks underlying remote spatial memory representation when encountering a similar experience.immediate early gene ͉ learning ͉ memory consolidation ͉ neurogenesis ͉ plasticity N ew neurons are generated throughout adult life in discrete regions of the mammalian brain, including the dentate gyrus (DG) of the hippocampus. Some of these newborn neurons become integrated into preexisting hippocampal circuits, raising the possibility that they may thereby contribute to behaviorally relevant neuronal assemblies. Supporting this idea, the increasing number of reports that have used correlative and invasive approaches indicates the existence of a functional link between hippocampal-dependent learning and adult hippocampal neurogenesis (1-5). Recently, it was found that new cells contribute to the functional activity patterns elicited in the hippocampus in response to performing memory tasks that solicit hippocampal networks (4, 6, 7).To date, the nature of the specific contributions of adultgenerated neurons to memory processing remains largely unknown. During the second week after birth, new hippocampal cells enter a period during which they show enhanced synaptic plasticity, their functional maturation occurs, and their ultimate survival is determined (8, 9). At this age, depletion of new neurons leads to memory impairment in several hippocampaldependent tasks (1, 3). Based on these observations, we sought to examine in mice injected with the birthdating marker 5-bromo-2Ј-deoxyuridine (BrdU) the contribu...