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Neurogenesis in the Adult

Gerd Kempermann1, Hongjun Song2, and Fred H. Gage3

1German Center for Neurodegenerative Diseases (DZNE) Dresden and CRTD—Center for Regenerative Therapies Dresden at Technische Universita¨t Dresden, 01307 Dresden, Germany 2Institute for Engineering, Program at ICW, The John Hopkins University, Baltimore, Maryland 21205 3Laboratory of Genetics LOG-G, The Salk Institute for Biological Studies, La Jolla, California 92037 Correspondence: [email protected]

Of the neurogenic zones in the adult , adult hippocampal attracts the most attention, because it is involved in higher cognitive function, most notably process- es, and certain affective behaviors. Adult hippocampal neurogenesis is also found in humans at a considerable level and appears to contribute significantly to hippocampal plasticity across the life span, because it is regulated by activity. Adult hippocampal neurogenesis generates new excitatory granule cells in the , whose form the mossy fiber tract that links the dentate gyrus to CA3. It originates from a population of radial -like precursor cells (type 1 cells) that have astrocytic properties, express markers of neural stem cells and divide rarely. They give rise to intermediate progenitor cells with first glial (type 2a) and then neuronal (type 2b) . Through a migratory -like stage (type 3), the newborn, lineage-committed cells exit the cell cycle and enter a maturation stage, during which they extend their dendrites into a the molecular layer and their to CA3. They go through a period of several weeks, during which they show increased , before finally becoming indistinguishable from the older granule cells.

ecause it has turned out that adult neuro- genesis, but reason enough to ask for the motifs Bgenesis not only exists in the human hippo- behind this interest. The answer, presumably, is campus but even seems to be restricted to it (see “function.” Adult hippocampal neurogenesis Spalding et al. 2013; Bergmann et al. 2015), adds particular functionality to the mammalian public and scientific attention to the phenom- hippocampus and presumably is involved in enon is soaring. In PubMed, search results for cognitive functions that we consider to be es- “” and “hippocampus” out- sential for humans. There is a price to pay for number those for “adult neurogenesis” and “ol- this type of plasticity. Adult neurogenesis is a factory bulb” or “subventricular” by 3:1. This complex multistep process, not a simple event. is no reason to neglect research on adult neuro- This review deals with the description of this genesis in the olfactory system, which is a nec- process and the restriction points at which reg- essary part of any holistic view on adult neuro- ulation occurs.

Editors: Fred H. Gage, Gerd Kempermann, and Hongjun Song Additional Perspectives on Neurogenesis available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a018812 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a018812

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G. Kempermann et al.

Adult neurogenesis is brain development re- distinction is awkward. Arguably, the contribu- capitulated in the adult and comprises a series tion of the dentate gyrus and the new of sequential developmental events that are all within it is critically important to overall hip- necessary for the generation of new neurons. pocampal function. As experiments suggest, In the original publications on adult neurogen- one can do quite well without adult neurogen- esis, the precursor cell population, from which esis, but certain advanced features, which might neurogenesis originates, could be identified explain the “evolutionary success” of the mam- only through the detection of their prolifera- malian dentate gyrus, depend on the new neu- tive activity and the absence of morphological rons (see Amrein 2015; Kempermann 2015). characteristics of mature neurons and later neu- The vote has, anyway, long been made by the ron-specific , such as NeuNorcalbindin scientific audience. We talk about adult hippo- (Altman and Das 1965; Kaplan and Hinds 1977; campal neurogenesis, when we mean neurogen- Cameron et al. 1993; Kuhn et al. 1996). The new esis in the adult dentate gyrus. neurons, in contrast, were identified by the pres- Adult hippocampal neurogenesis generates ence of mature neuronal markers in cells that only one type of : granule cells in the had been birthmarked with the or dentate gyrus. To date, there is no conclusive BrdU method (see Kuhn et al. 2015) a couple evidence that other neuronal cell types could of weeks earlier. The expression of polysialilated be generated under physiological conditions, neural-cell-adhesion molecule (PSA-NCAM) although some as-yet unconfirmed claims have with neurogenesis has been noted early but been made (Rietze et al. 2000; Liu et al. 2003). could not be clearly linked to either proliferation Granule cells are the excitatory principal neu- or the mature stage (Seki and Arai 1993a,b). rons of the dentate gyrus. They receive input PSA-NCAM expression was the first indication from the entorhinal cortex and send their axo- of the developmental events that take place, fill- nal projection along the mossy fiber tract to area ing the gaps between the start and endpoint of CA3, where they terminate in large - and development. Today, we have quite detailed -rich structures, the so-called “bou- knowledge about the course of neuronal devel- tons.” They provide excitatory input to the py- opment in the adult hippocampus and, al- ramidal cells of CA3. They fire very sparsely and though many detailed questions are open, aclear their activity is modulated by a large number of overall picture has emerged (Kempermann et al. in the dentate gyrus and hilus area. 2004; Abrous et al. 2005; Ming and Song 2005; The precursor cells, from which adult neurogen- Lledo et al. 2006). Weoften even use doublecor- esis originates, reside in a narrow band of tissue tin (DCX), which shows a complete overlap in between the layer and the hilus, the expression with PSA-NCAM in the hippocam- so-called (SGZ). The term was pus,assurrogatemarkersforadult neurogenesis. coined by the discoverer of adult hippocampal This is sometimes questionable because the pro- neurogenesis, Joseph Altman in 1975. The orig- cess is not identical to the end result, the exis- inal description of adult neurogenesis in the tence of mature new neurons, but it is also tell- brain was published in 1965 by Joseph ing. A plasticity marker is widely considered as Altman and his colleague Gopal Das (Altman representative of the whole process and its result. and Das 1965). Although we often simply talk of neurogen- The SGZ contains the microenvironment esis in the hippocampus, precisely, neurogenesis that is permissive for neuronal development to occurs only in the dentate gyrus, not in other occur. Analogous to other stem cell systems subregions; and, in an older nomenclature, the in the body, this microenvironment is called dentate gyrus is not even part of the hippocam- the neurogenic “niche.” The niche comprises pus proper (but the “hippocampal formation”). the precursor cells themselves, their immediate Although there are justifications to exclude the progeny and immature neurons, other glial cells dentate gyrus from the hippocampus, we be- and endothelia, very likely immune cells, micro- lieve that, from any functional perspective, this glia, and macrophages, and an extracellular ma-

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Adult Hippocampal Neurogenesis

trix. According to one study, the niche is sur- ment (Ge et al. 2007a), but, at a later stage, the rounded by a common basal membrane (Mer- balance between inhibition and excitation also cier et al. 2002). Because of the prominent role determines that the new neurons preferentially that the vasculature appears to play in this con- respond to incoming stimuli, biasing activity text, the neurogenic niche has also been called toward the new neurons (Marin-Burgin et al. the “vascular niche” (Palmer et al. 2000). 2012). The type 1 precursor cells, from which adult neurogenesis originates, have endfeet on the DISTINCT STEPS OF NEURONAL vasculature in the SGZ (Filippov et al. 2003), DEVELOPMENT vascular endothelial growth factor (VEGF) is a potent regulator of adult neurogenesis (Jin et al. Adult neurogenesis can be divided into four 2002; Scha¨nzer et al. 2004), and a complex re- phases: a precursor cell phase, an early survival lationship exists between endothelial cells and phase, a postmitotic maturation phase, and a hippocampal precursor cells (Wurmser et al. late survival phase. Based on cell morphology 2004). The niche provides a unique milieu con- and a set of marker , six distinct mile- sisting of extracellular matrix, short- and long- stones can be identified, which to date still range humoral factors, and cell-to-cell contacts, somewhat overemphasize the precursor cell which allow neuronal development to occur in a stages of adult neurogenesis (Fig. 1) (Kemper- controlled fashion (“neurogenic permissive- mann et al. 2004; Steiner et al. 2006). From a ness”). Local play a key role in pro- radial glia-like precursor cell, adult neurogene- moting neurogenesis. In vivo, the developing sis progresses over three identifiable progenitor cells show a close spatial relationship with astro- stages associated with high proliferative activity cytes (Shapiro et al. 2005; Plu¨mpe et al. 2006). to a postmitotic maturation phase and, finally, Ex vivo, astrocytes and -derived factors the existence of a new granule cell (Brandt et al. were potent inducers of neurogenesis from hip- 2003; Filippov et al. 2003; Fukuda et al. 2003; pocampal precursor cells (Song et al. 2002; Bar- Encinas et al. 2006; Steiner et al. 2006). Al- kho et al. 2006). though on the precursor cell stage and early The SGZ is also special in that it receives after cell-cycle exit, large changes in cell num- synaptic input from various other brain regions: bers occur and the effects of development be- dopaminergic fibers from the ventral tegmental come more qualitative at later times. area, serotonergic projections from the raphe The precursor cell phase serves the expan- nuclei, acetylcholinergic input from the sep- sion of the pool of cells that might differentiate tum, and g-aminobutyric acid (GABA)ergic into neurons. The early survival phase marks the connections from local interneurons. In addi- exit from the cell cycle. Most newborn cells are tion, there are commissural fibers from the con- eliminated within days after they are born. The tralateral side. Manipulations of all the different postmitotic maturation phase is associated with and input systems, for exam- the establishment of functional connections, ple, by lesioning studies to the input structures the growth of axon and dendrites, and synapto- or pharmacological intervention, have revealed genesis. The late survival phase represents a pe- a regulatory effect on adult neurogenesis, al- riod of fine-tuning. It has been estimated that though the level of resolution is still too low to the entire period of adult neurogenesis takes identify the relative specific contributions of the  7 wk. Characteristic electrophysiological pat- individual systems to the control of adult neuro- terns allow the assignment of functional states genesis (Bengzon et al. 1997; Cooper-Kuhn et al. to the morphologically distinguishable steps of 2004; Dominguez-Escriba et al. 2006) and to development. understand how the variety of stimuli is inte- One central question in research on adult grated. Nevertheless, the role of interneurons is hippocampal neurogenesis is how far it is sim- critical in more than one regard. First, ambient ilar to or distinct from embryonic and early and synaptic GABA drives neuronal develop- postnatal neurogenesis in the dentate gyrus.

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G. Kempermann et al.

Precursor cell stage Radial glia-like stem cell GFAP Type 1 BLBP GFAP+/– Type 2a Nestin BLBP Transiently Type 2 Sox2 amplifying progenitor cells Type 2b Nestin DCX Expansion phase PSA-NCAM NeuroD Prox1 Type 3 DCX PSA-NCAM NeuroD Prox1 GABAergic input

Early postmitotic Calretinin maturation phase NeuN DCX Dendrite extension PSA-NCAM Axon extension NeuroD Increased synaptic plasticity Prox1 Activity-dependent recruitment Survival or apoptosis

Late postmitotic Calbindin maturation phase NeuN NeuroD Maturation of Prox1 dendritic spines Lowered threshold for LTP, increased synaptic plasticity Survival and elimination phase Glutamatergic input

Figure 1. Developmental stages in the course of adult hippocampal neurogenesis (see text for details). GFAP, Glial fibrillary acidic ; BLBP, brain lipid-binding protein; DCX, ; PSA-NCAM, polysialilated neural-cell-adhesion molecule; LTP, long-term potentiation.

The dentate gyrus develops in three distinctive generated neurons behave highly similar to waves of development, of which adult neuro- those produced during the neonatal period, genesis is the last (Altman and Bayer 1990a,b). suggesting a homogenous population. On the The bulk of dentate gyrus neurons is produced other hand, quality and quantity of extrinsic at around P7. From a functional perspective, stimuli and memory contents that pass the den- Laplagne et al. (2006) have argued that adult- tate gyrus will be dramatically different between

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Adult Hippocampal Neurogenesis

postnatal and adult periods. Also, the speed of these cells are true stem cells, in the sense that maturation might differ (Overstreet-Wadiche et their capacity for self-renewal is “unlimited,” al. 2006a), although with respect to the influ- has been disputed by others (Seaberg and van ence of extrinsic stimuli (here, ) on dif- der Kooy 2002; Bull and Bartlett 2005), but ferentiation speed, the data are not consistent methodological and strain differences between (Jakubs et al. 2006; Overstreet-Wadiche et al. the studies prevented closing the case. After 2006b; Plu¨mpe et al. 2006). careful microdissection of dentate gyrus tissue and by the use of an enrichment procedure, it was found that the murine dentate gyrus in fact THE PRECURSOR CELL PHASE contained “stem cells” in the stricter sense of the A number of morphologically identifiable definition (Babu et al. 2007). A similar discus- “types” of precursor cells are involved in the sion arose in vivo, in which two studies asked course of adult hippocampal neurogenesis. whether the radial glia-like type 1 cells are capa- Such cell types do not actually constitute distinct ble of both asymmetric and symmetric divi- populations of cells but rather reflect milestones sions. Encinas and colleagues presented a model of a developmental process. in which the potential of the precursor cells is Adult hippocampal neurogenesis originates fixed and the precursor cell population becomes from a population of precursor cells with glial exhausted with advancing age (Encinas et al. properties. A subset of these shows morpholog- 2011). This finding was contrasted by a study ical and antigenic characteristics of radial glia. by Bonaguidi et al. (2012), which discovered Their cell body is found in the SGZ and the that the range of possible behaviors is actually process extends into the molecular layer. Not much larger at the level of individual cells. Both all radial elements show the same markerexpres- studies might be correct, but show different as- sion and some markers for radial glia during pects of the same issue. If adequately stimulated, are absent. The astro- the precursor cells might switch their program cytic nature of hippocampal precursor cells was and allow the long-term maintenance of the first shown by Seri, Alvarez-Buylla, and col- precursor cell pool, which is lost in the case of leagues (2001), when they suppressed cell divi- inactivity. This idea is plausible in the context of sion by application of a cytostatic drug and other aspects of the activity-dependent regula- found that the first cells that reappeared were tion of adult neurogenesis but remains to be proliferative astrocyte-like cells with radial mor- tested (Kempermann 2011a). Precursor cells in phology. The second line of evidence came from the adult hippocampus, however, are heteroge- experiments in which the receptor for an avian neous in their properties even at the apparent virus was expressed under the of glial “stages” that can be more or less readily identi- fibrillaryacidic protein (GFAP) or nestin, so that fied (Bonaguidi et al. 2012). astrocyte-like or nestin-expressing cells could With that caveat in mind, the radial glia-like specifically be infected by an otherwise inert vi- type 1 cells of the hippocampus give rise to in- rus. Transduced cells generated new neurons in termediate progenitor cells, type 2 cells. These vivo, demonstrating the developmental poten- show a high proliferative activity. A subset of tial in vivo (Seri et al. 2001, 2004). The study these cells still expresses glial markers but lack related to similar experiments in the subventric- the characteristic morphology of radial cells ular zone (SVZ)/ (OB) system (type 2a). On the level of type 2 cells that, to- (Doetsch et al. 1999a,b; Laywell et al. 2000). gether with type 1 cells, express intermediate Ex vivo, hippocampal precursor cells were filament nestin, first indications of neuronal lin- first isolated by Ray et al. (1993) from the em- eage choice appear. These markers comprise, bryonic brain and by Palmer et al. (1995) from among others, factors NeuroD1 the adult rat brain. In culture, the precursor cells and Prox1. This cellular phenotype has been show signs of stemness (self-renewal and multi- called atype 2b cell (Steineret al. 2006). Of these, potency) (Palmer et al. 1997). To which degree Prox1 is specific to granule cell development.

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Manipulation of Prox1 abolishes adult neuro- control of GABA that comes from the local par- genesis at this stage (Karalay et al. 2011). Type valbumin-expressing interneurons (basketcells) 2 cells are also characterized by their expression (Song et al. 2012; Moss and Toni 2013). In any of Eomes (Tbr2), a that, case, during their development, the new cells are during embryonic cortical development, identi- first responsive to ambient GABA, and more re- fies the basal progenitor cells, which maintain spond to synaptic excitatory GABAergic input. self-renewing properties and can differentiate Type 2 cells respond to physiological into neurons (Hodge et al. 2008). Tbr2 appears stimuli, such as voluntary wheel running (Kro- to suppress Sox2 and is critical for the transition nenberg et al. 2003), or pharmacological stim- from stem cells to intermediate progenitor cells ulation via -dependent mechanisms (Hodge et al. 2012b). (Encinas et al. 2006). Again, it seems to be A point-by-point comparison between GABA that sets the pace for this regulation (Ge adult neurogenesis and fetal and early postnatal et al. 2007a). neurogenesis in the dentate gyrus is still lacking, Among the neuronal lineage markers first but many transcription factors involved in em- appearing at the type 2b stage is DCX. DCX is bryonic cortical and hippocampal development expressed at the proliferative stage, even after are also involved in adult hippocampal neuro- nestin has been down-regulated (type 3 cells). genesis (Li and Pleasure 2005; Hodge et al. Normally, type 3 cells show only little prolifer- 2012a). Insight into the transcriptional control ative activity. Under pathological conditions, of the initiation of neuronal differentiation is however, such as experimental seizures, they scarce. From the available data, however, it is can show a disproportional increase in cell di- obvious that if a fate choice decision is made vision (Jessberger et al. 2005). DCX expression at all, it must occur on the level of the type 2a extends from a proliferation stage, through cell- cells. All later cells express NeuroD1 and Prox1 cycle exit, to a period of postmitotic maturation and there is no overlap between NeuroD1 and that lasts 2 to 3 wk (Brandt et al. 2003; Rao Prox1 and astrocytic markers at any time point. and Shetty 2004; Couillard-Despres et al. 2005; Tailless (Tlx) is a key candidate for a transcrip- Plu¨mpe et al. 2006). DCX shows an almost tion factor involved in controlling the transition complete overlap with PSA-NCAM and is a between glial and neuronal of the widely used surrogate marker for adult neuro- precursor cells (Shi et al. 2004), and so are Prox1 genesis. Strikingly, despite its prominent ex- and NeuroD1 themselves (Liu et al. 2000; Gao pression, DCX does not seem to be required et al. 2009; Karalay et al. 2011). Beckervorder- for normal neuronal development in the adult sandforth et al. (2015) covers the transcriptional hippocampus (Merz and Lie 2013). control of hippocampal neurogenesis in greater detail. THE EARLY SURVIVAL PHASE On the level of type 2 cells, the developing cells also receive first synaptic input, which is Very early after cell-cycle exit, the new neurons GABAergic (Tozuka et al. 2005; Wang et al. express postmitotic markers, such as NeuN 2005). A more recent study, however, suggests (RbFox3), and the transient marker calretinin that type 1 cells also express GABAA receptors (Brandt et al. 2003). Because type 3 cells are still throughout and AMPA receptors only in their proliferative, NeuN can be found in some cells processes with no ionotropic glutamate recep- as early as 1 d after the injection of the prolifer- tors (Renzel et al. 2013). Although type 1 cells ation marker. The protein is a splice factor of can respond to extrinsic stimuli by increasing unknown specific function in this context. The cell proliferation (Huttmann et al. 2003; Kunze number of NeuN-positive new neurons is high- et al. 2006; Weber et al. 2013), the burden of est at very early time points and decreases dra- expansion lies on the type 2 cells. The radial cells matically within a few days. This elimination represent the largely quiescent compartment, process is apoptotic (Biebl et al. 2000; Kuhn and the control of quiescence is also under the et al. 2005). Thus, the majority of cells is elim-

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inated well before they have made functional plus of new neurons, and that only a very small connections in the target area in CA3 or re- proportion survives for long periods of time ceived correct dendritic input from the entorhi- (Kempermann et al. 2003). It seems that cells nal cortex in the molecular layer of the dentate that have survived the first 2 wk will be stably gyrus. Besides BDNF signaling as the main sus- and persistently integrated into the network of pect and the contribution of several neurotrans- the dentate gyrus for a very long time. After this mitter systems (Tashiro et al. 2006), a number of time point, only very small changes in cell num- other “survival factors” have been identified ber occur. One consequence of this observation (e.g., among others, p63 [Cancino et al. 2013], is that adult neurogenesis, lifelong, contributes Hspb8 [Ramı´rez-Rodrı´guez et al. 2013], and to growth of the dentate gyrus and does not NF-kB [Imielski et al. 2012]), so that the overall replace older cells (Crespo et al. 1986), although mechanistic picture is far from clear. this growth has not been proven at later life stag- The initiation of dendrite development after es, when the levels of adult neurogenesis are very the time point of cell-cycle exit appears to be low. For the first year in the life of a rodent, highly variable. The time course of dendritic growth has been shown in several studies (Alt- development itself, in contrast, seems to follow man and Das 1965; Bayer et al. 1982; Boss et al. a rather fixed temporal course. Within days after 1985), but a modern stereological account is still cell-cycle exit, the new cells send their axon to lacking. A study based on genetic lineage tracing target area CA3, where they form appropriate suggested that, in mice, 30% of the granule (Sun et al. 2013). Accordingly, this cells are generated after birth and during adult- phase is associated with the expression of col- hood (Ninkovic et al. 2007). This number is lapsing-response mediator protein (Crmp, also close to the estimated turnover fraction in the known as TOAD-64 or TUC-4), a molecule in- human hippocampus (Spalding et al. 2013). volved in axon path finding. The newborn neu- Along similar lines of reasoning, it seems rons also express the embryonic tau isoform, that stimuli that control the expansion phase which is otherwise not present in the adult brain tend to be rather nonspecific (e.g., the pan- (Bullmann et al. 2010). The axons of the new synaptic activation in seizures, physicalactivity), neurons are part of the mossy fiber tract, whose whereas stimuli that are more specific to the hip- high level of plasticity has been noted early on pocampus in that they reflect hippocampus-de- but had not been brought into connection with pendent function affect the survival phases. On adult neurogenesis. Today, we know that the a quantitative level, this has been shown only for axonal plasticity that characterizes the mossy the early postmitotic period. Exposure to the fiber tract to a large degree depends on the complexity of an enriched environment or, at new neurons (Ro¨mer et al. 2011). least in some studies, to stimuli of hip- The main synaptic input to the new cells is pocampus-dependent learning tasks increase still GABAergic at this stage and GABA remains survival at this stage (Gould et al. 1999; Do- excitatory. GABA switches to its inhibitory brossy et al. 2003). Presumably, similar effects function only, when sufficient glutamatergic are found at later stages as well but so far have contact has been made and, presumably, when not been measurablewith the available methods. the cells have begun to develop their own gluta- (For more details on the mechanisms underly- matergic neurotransmitter phenotype (Tozuka ing cell-cycle exit, migration, and early matura- et al. 2005). GABA action itself drives neuronal tion, please refer to Toni and Schinder 2015.) maturation in these cells and steers the synaptic integration (Ge et al. 2006). POSTMITOTIC MATURATION PHASE Quantitatively, most of the regulation oc- curs at this stage of neuronal development, not Serendipitously, it was found that the maturing in the expansion phase as it is often assumed cells up-regulate promoter activity of pro-opio- (Kempermann et al. 2006). The reason is that melanocortin (POMC), although the protein is precursor cell proliferation generates a vast sur- not detectable in these cells. A transgenic mouse

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G. Kempermann et al.

line expressing green fluorescent protein (GFP) synapses in the mossy fiber boutons (Toni et al. under the POMC promoter has become a useful 2008). tool to study the electrophysiology of the im- Functional maturation of the new neurons mature neurons (Overstreet et al. 2004). At this has now been characterized to a considerable stage, depolarizing GABA is required to allow degree (van Praag et al. 2002; Ambrogini et al. the formation of glutamatergic synapses (Chan- 2004; Schmidt-Hieber et al. 2004; Esposito et cey et al. 2013), comparable to the situation in al. 2005; Couillard-Despres et al. 2006; Marin- the developing cortex (Wang and Kriegstein Burgin et al. 2012). The cells progress from a 2008). The exact timing of the maturation is state with high input resistance to the normal dependent on the activity in local circuits, fur- membrane properties of mature granule cells. ther supporting the idea that adult hippocam- (For more details on the functional maturation pal neurogenesis is controlled by activity at nu- of the new neurons, please refer to Toni and merous stages of neuronal development (Piatti Schinder 2015 and Song et al. 2015.) et al. 2011). Details of spine development have largely LATE MATURATION PHASE been investigated by transducing a proliferating cell with a GFP-expressing retrovirus (Fig. 2) We presently know the least about the adaptive (Zhao et al. 2006). From these experiments, changes that occur late in neuronal develop- we know that axon elongation precedes spine ment of adult neurogenesis. The period of cal- formation on the dendrites and both are orches- retinin expression lasts only 3 to 4 wk, rough- trated in a precise and complex way (Sun et al. ly consistent with the temporal pattern of 2013). Although axonal contact to CA3 is made dendritic maturation. Presumably, after full 10 d after labeling the proliferative cells, the structural integration into the existing network, first spines appear almost a week later. To con- the new cells switch their calcium-binding pro- nect to the target cells in CA3, the axons of the tein from calretinin to calbindin (Brandt et al. new neurons enter a competition with existing 2003). Still, it takes several more weeks until the

Figure 2. Dendrite development of newborn neurons in the dentate gyrus. Proliferating precursor cells in the subgranular zone (SGZ) were labeled with a green fluorescent protein (GFP)-expressing retrovirus and analyzed at later time points. Here, GFP-positive new granule cells can be seen at 2 wk (16 d after injection, left) and 4 wk (28 d after injection, right). During the early postmitotic maturation phase, the cells develop the full morphology of hippocampal granule cells. It is noteworthy that the cells might show a slightly different pace of maturation. After 4 wk, many cells have extended its dendritic tree far into the molecular layer. First dendritic spines can be seen on the dendrites (see Zhao et al. 2006, for details of dendritic development in adult hippocampal neurogenesis). Scale bar, 15 mm. (The figure is contributed by Chunmei Zhao, Salk Institute.)

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new cells have become electrophysiologically in- is made to tie these distinct molecular mecha- distinguishable from their older neighbors (van nisms to the identifiable stages of development. Praag et al. 2002; Ambrogini et al. 2004). Once On the level of the precursor cells, basic he- glutamatergic synaptic connections have been lix–loop–helix factor Sox2 characterizes the made, the new neurons go through a phase of stem-like cells with glial properties (D’Amour increased synaptic plasticity. The threshold to and Gage 2003; Steiner et al. 2006). Overlap be- induce long-term potentiation (LTP)in the im- tween Sox2 and early neuronal markers is min- mature neurons is lower than in mature granule imal. However, Sox2 is also found in S100b-pos- cells (Wang et al. 2000; Schmidt-Hieber et al. itive astrocytes without precursor cell function. 2004). In fact, the only LTP measurable from Sox2 expression is tightly regulated and critical the dentate gyrus under normal (i.e., inhibited) for the balance between proliferation and differ- conditions originates from the newborn neu- entiation (Julian et al. 2013). rons, which are not yet inhibited by the local The transition between glial and neuronal interneurons (Saxe et al. 2006; Garthe et al. phenotypes might be controlled by Tlx (Shi 2009). These particular properties biasthe input et al. 2004) and Ascl1. The earliest known neu- toward the new neurons (Marin-Burgin et al. ronal factor is NeuroD1, which is recognized by 2012). a binding motif in the promoter region of the This lasts from 1 to 1.5 mo Dcx (Steiner et al. 2006). Parallel to Neu- after the cells were generated (Ge et al. 2007b). roD1, Prox1 is found. Prox1 is highly specific to Some theories about the potential function of granule cells (Pleasure et al. 2000). the new granule cells build on this fact by argu- This set of transcription factors is different ing that the altered plastic properties help the from the subventricular system, in which Pax6, dentate gyrus to encode temporal information Dlx, and Olig2 play prominent roles. Expression into to be stored (Aimone et al. of Pax6 has been noted in the dentate gyrus as 2006). Alternatively, the increased plasticity well (Nacher et al. 2005), but its function is not might serve the purpose of facilitating preferen- clear yet. Olig2 is expressed in the dentate gyrus tial integration of the new cells to achieve long- but in cells outside the lineage, which leads to term changes in the network (Wiskott et al. granule cell development. It is, thus, assumed 2006). Possibly, both ideas are correct, and a that new in the adult dentate specific transient function prepares the ground gyrus, which are very rare anyway (Kemper- for an equally specific long-term function. Pre- mann et al. 2003; Steiner et al. 2004), originate sumably, important regulatory events take place from a distinct pool of precursor cells that are at this stage, but they will be effective more on a characterized by their expression of proteogly- qualitative level than on a quantitative one. can NG2.

CONTROL OF NEURONAL DEVELOPMENT REGULATION AND FUNCTION OF ADULT HIPPOCAMPAL NEUROGENESIS The inherent mechanisms that constitute the process of neuronal development have to be Although there is no consistent use of the ter- distinguished from regulatory events that act minology, “control” and “regulation” of a bio- on these mechanisms. Transcriptional control logical process are not identical (Kempermann of adult neurogenesis represents the backbone 2011b). Regulation means those processes that of neuronal development. Regulatory events do act on the basic mechanisms that control neuro- not change this backbone but modulate it and genesis. Regulation thus encompasses processes rely on its maintained integrity. Transcriptional on many conceptual levels, from behavioral control thereby represents the shared target of down to molecular. Quantitatively, regulation regulation. These mechanisms are described of adult hippocampal neurogenesis mostly oc- and discussed in Beckervordersandforth et al. curs on the level of survival of the newborn cells. (2015). In the following paragraph, the attempt Between 30 inbred strains of mice, the genetical-

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ly determined level of survival explained 85% of selective postmitotic survival is dependent on the variance found in net neurogenesis, whereas specific, hippocampus-dependent stimuli and cell proliferation explained only 19% (Kemper- accounts for the greatest part of the neurogen- mann et al. 2006). On the other hand, numerous ic regulation. Morphological maturation finds studies reported examples of factors that influ- its most visible expression in the extension of ence cell proliferation. The current hypothesis the dendrites and the emergence of dendritic is that this broad sensitivity of precursor cell spines. GABAergic input, first ambient, later proliferation is nonspecific, whereas survival- synaptic, promotes neuronal maturation until promoting effects depend on specifically hip- regular glutamatergic input from the entorhinal pocampal functional stimuli. Lucassen et al. cortex sets in. In a brief postmitotic interval, (2015), Kuhn (2015), and Song et al. (2015) during which the new cells express calcium buf- expand on this idea. fering protein calretinin, the new neurons also The key point is, as already alluded to at extend their axon to area CA3. This phase of various points during this review, that adult early synaptic integration is also characterized hippocampal neurogenesis is an activity-depen- by increased synaptic plasticity, presumably dent process, during which macroscopic behav- facilitating the survival-promoting effects of ior of the individual is translated into changes at functional integration. At present, little is the systems and network level, which in turn known about the details of neuronal matura- affects local circuitry and humoral and other tion, but it seems that after a period of 7 wk, signaling systems that affect the control of adult the new neurons become indistinguishable neurogenesis. The complexity of this cellular from their older neighbors. A number of tran- plasticity is amazing and hardly understood to scription factors have been identified that can be date. The consequential insight, however, is in- linked to particular stages of neuronal develop- evitable. Functions of the new neurons, as far as ment in the adult hippocampus, for example, they result in any meaningful changes in behav- granule-cell-specific factor Prox1 that is ex- ior or “activity,” cannot be separated from reg- pressed very early on the level of type 2 progen- ulation and vice versa. The link between the two itor cells and remains expressed in mature gran- lies at the heart of adult neurogenesis and is the ule cells. very essence of “plasticity.”

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14 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a018812 Downloaded from http://cshperspectives.cshlp.org/ at UNIV OF PENNSYLVANIA LIBRARY on August 30, 2017 - Published by Cold Spring Harbor Laboratory Press

Neurogenesis in the Adult Hippocampus

Gerd Kempermann, Hongjun Song and Fred H. Gage

Cold Spring Harb Perspect Biol 2015; doi: 10.1101/cshperspect.a018812

Subject Collection Neurogenesis

Adult Neurogenesis and Psychiatric Disorders Adult Olfactory Bulb Neurogenesis Eunchai Kang, Zhexing Wen, Hongjun Song, et al. Pierre-Marie Lledo and Matt Valley Neuronal Circuitry Mechanisms Regulating Adult Adult Neurogenesis in Fish Mammalian Neurogenesis Julia Ganz and Michael Brand Juan Song, Reid H.J. Olsen, Jiaqi Sun, et al. Neurogenesis in the Developing and Adult Brain In Vitro Models for Neurogenesis −−Similarities and Key Differences Hassan Azari and Brent A. Reynolds Magdalena Götz, Masato Nakafuku and David Petrik Genetics and in Adult Neurogenesis Engineering of Adult Neurogenesis and Jenny Hsieh and Xinyu Zhao Benedikt Berninger and Sebastian Jessberger The Adult Ventricular−Subventricular Zone Computational Modeling of Adult Neurogenesis (V-SVZ) and Olfactory Bulb (OB) Neurogenesis James B. Aimone Daniel A. Lim and Arturo Alvarez-Buylla Diversity of Neural Precursors in the Adult Control of Adult Neurogenesis by Short-Range Mammalian Brain Morphogenic-Signaling Molecules Michael A. Bonaguidi, Ryan P. Stadel, Daniel A. Youngshik Choe, Samuel J. Pleasure and Helena Berg, et al. Mira Detection and Phenotypic Characterization of Adult Neurogenesis: An Evolutionary Perspective Adult Neurogenesis Gerd Kempermann H. Georg Kuhn, Amelia J. Eisch, Kirsty Spalding, et al. Maturation and Functional Integration of New Epilepsy and Adult Neurogenesis Granule Cells into the Adult Hippocampus Sebastian Jessberger and Jack M. Parent Nicolas Toni and Alejandro F. Schinder

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