Delayed Development of Adult-Generated Granule Cells in Dentate Gyrus

Overstreet-Wadiche, Linda; Bensen, Ae Soon L.; Westbrook, Gary L.

doi:10.1523/jneurosci.4111-05.2006

Cited by 164 publications

(149 citation statements)

References 56 publications

(84 reference statements)

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“…In the hippocampus, the maturation of granule cells takes ~10 days during neonatal development or 3 weeks during adult neurogenesis (Overstreet-Wadiche et al, 2006). Our study found that the neuronal identity of DG cells was bi-potent during the late stages of these extended periods.…”

Section: Neuronal Phenotype Plasticity In Postmitotic Dg Cellsmentioning

confidence: 54%

Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus

Iwano¹,

Masuda²,

et al. 2012

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The brain is composed of diverse types of neurons that fulfill distinct roles in neuronal circuits, as manifested by the hippocampus, where pyramidal neurons and granule cells constitute functionally distinct domains: cornu ammonis (CA) and dentate gyrus (DG), respectively. Little is known about how these two types of neuron differentiate during hippocampal development, although a set of transcription factors that is expressed in progenitor cells is known to be required for the survival of granule cells. Here, we demonstrate in mice that Prox1, a transcription factor constitutively expressed in the granule cell lineage, postmitotically functions to specify DG granule cell identity. Postmitotic elimination of Prox1 caused immature DG neurons to lose the granule cell identity and in turn terminally differentiate into the pyramidal cell type manifesting CA3 neuronal identity. By contrast, Prox1 overexpression caused opposing effects on presumptive hippocampal pyramidal cells. These results indicate that the immature DG cell has the potential to become a granule cell or a pyramidal cell, and Prox1 defines the granule cell identity. This bi-potency is lost in mature DG cells, although Prox1 is still required for correct gene expression in DG granule cells. Thus, our data indicate that Prox1 acts as a postmitotic cell fate determinant for DG granule cells over the CA3 pyramidal cell fate and is crucial for maintenance of the granule cell identity throughout the life.

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Section: Neuronal Phenotype Plasticity In Postmitotic Dg Cellsmentioning

confidence: 54%

Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus

Iwano¹,

Masuda²,

et al. 2012

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“…Growth of both dendrites and axons of adult-born neurons occurs more slowly in the adult hippocampus (8)(9)(10). In the developing rodent brain, mossy fiber boutons reach maturity by the beginning of the third postnatal week, when the oldest granule cells in the hippocampus would be Ϸ4 weeks of age (16).…”

Section: Discussionmentioning

confidence: 99%

“…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

Proc. Natl. Acad. Sci. U.S.A.

192

179

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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...

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“…Newborn GCs fire small-amplitude action potentials which may be unable to evoke transmitter release (Overstreet-Wadiche et al, 2006). We therefore examined the firing properties of GAD67-expressing GCs in juvenile G42 mice.…”

Section: Resultsmentioning

confidence: 99%

Presynaptic But Not Postsynaptic GABA Signaling at Unitary Mossy Fiber Synapses

Cabezas

Irinopoulou²,

Gauvain³

et al. 2012

J. Neurosci.

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Dentate gyrus granule cells have been suggested to corelease GABA and glutamate both in juvenile animals and under pathological conditions in adults. Although mossy fiber terminals (MFTs) are known to express glutamic acid decarboxylase (GAD) in early postnatal development, the functional role of GABA synthesis in MFTs remains controversial, and direct evidence for synaptic GABA release from MFTs is missing. Here, using GAD67-GFP transgenic mice, we show that GAD67 is expressed only in a population of immature granule cells in juvenile animals. We demonstrate that GABA can be released from these cells and modulate mossy fiber excitability through activation of GABAB autoreceptors. However, unitary postsynaptic currents generated by individual, GAD67-expressing granule cells are purely glutamatergic in all postsynaptic cell types tested. Thus GAD67 expression does not endow dentate gyrus granule cells with a full GABAergic phenotype and GABA primarily instructs the pre-rather than the postsynaptic element.

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Delayed Development of Adult-Generated Granule Cells in Dentate Gyrus

Cited by 164 publications

References 56 publications

Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus

Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus

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

Presynaptic But Not Postsynaptic GABA Signaling at Unitary Mossy Fiber Synapses

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