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Cited by 236Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

Adult neurogenesis, glia, and the extracellular matrix

Open access
Cope, Elise C., Gould, Elizabeth·2019·Cell Stem Cell
DOI 10.1016/j.stem.2019.03.023PMC PMC7961263
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Abstract

In the adult mammalian hippocampus, new neurons arise from stem and progenitor cell division, a process known as adult neurogenesis. Adult-generated neurons are sensitive to experience and may participate in hippocampal functions, including cognition, anxiety/stress regulation, and social behavior. Increasing evidence emphasizes the importance of new neuron connectivity within the hippocampal circuitry for understanding the impact of adult neurogenesis on brain function. In this Review, we discuss how the functional consequences of new neurons arise from the collective interactions of presynaptic and postsynaptic neurons, glial cells, and the extracellular matrix, which together form the “tetrapartite synapse”.

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Written from the paper’s full text.

TL;DR

This review argues that adult hippocampal neurogenesis and its functional effects depend on new neuron connectivity within the “tetrapartite synapse,” comprising pre- and postsynaptic neurons, glia, and extracellular matrix. It synthesizes rodent evidence showing that experience and pathology alter new neuron production, integration, and behavior, with glia and ECM as key regulators.

Key findings

  • Adult hippocampal neurogenesis produces dentate gyrus granule cells; as many as 9,000 new granule cells are added daily to the young adult rat dentate gyrus. New neurons receive GABAergic inputs first, then glutamatergic input from hilar mossy cells, then entorhinal cortical input, and strongly resemble developmentally generated granule cells by 4–6 weeks post-mitosis.
  • Adult-born neurons have been linked to hippocampal cognition, anxiety/stress regulation, social behavior, and pattern separation, but direct manipulations often yield inconsistent results; some studies find no effect of reduced neurogenesis, effects only on certain cognitive tests, or even improved cognitive function after ablation.
  • More new neurons are not always beneficial: stroke, seizure, and blunt trauma increase adult neurogenesis yet are associated with reduced cognitive function; inhibiting neurogenesis reduces chronic seizures and seizure-related cognitive decline as well as stroke-induced cognitive decline. Fluoxetine-induced overproduction of new neurons was associated with cognitive decline, increased susceptibility to stress-induced depression, and excessive anxiety.
  • Rewarding experiences such as voluntary exercise, environmental enrichment, and sexual experience enhance adult neurogenesis and hippocampal function, whereas aversive stress, aging, and parenting suppress it. Glia and ECM components—including chondroitin sulfate proteoglycans, reelin, MMP9, tenascin-R, and perineuronal nets—regulate new neuron number, migration, dendritic maturation, synapse formation/elimination, and plasticity; ECM is noted to compose approximately 20% of brain volume.

Methods

  • Narrative review; no primary experimental data or sample. It synthesizes published rodent studies except where otherwise stated.
  • Focuses on adult hippocampal neurogenesis and the tetrapartite synapse, citing evidence on stem/progenitor division, new neuron integration, behavior, glia, ECM, and perineuronal nets; includes Table 1 and Figures 1–4.
  • Main analysis is qualitative synthesis of cited literature; no systematic review, meta-analysis, or new statistical analysis is reported.

Limitations

  • Stated: the extent of adult neurogenesis in humans remains debated, with some studies contradicting positive findings; direct manipulations of adult neurogenesis often produce inconsistent behavioral results.
  • Stated gaps: several areas are relatively uninvestigated, including how enriched environment alters axon connections of adult-generated neurons, effects of sexual experience on stem cells and connectivity, PNNs in adult neurogenesis, MMPs in intact adult neurogenesis, and the extent to which glia influence functional connectivity of new neurons.
  • Evident: as a narrative review relying largely on rodent studies, it cannot establish causality or quantify effect sizes; conclusions depend on the selection and interpretation of cited literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.stem.2019.03.023

Cites

207 of 207 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Beginning less than 1 week after their generation, new granule cells extend mossy fiber axons through the hilus toward the CA3 and CA2 subregions.

    “Beginning less than 1 week after their generation, new granule cells extend axons, known as mossy fibers, through the hilus toward the CA3 and CA2 subregions of the hippocampus (Llorens-Martín et al., 2015; Zhao et al., 2006).”
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    Electrophysiological studies show that new cells produced in the adult dentate gyrus can generate action potentials within a week post-mitosis.

    “Electrophysiological studies of new cells produced in the adult dentate gyrus have shown that this capability emerges relatively quickly (within a week) post-mitosis.”
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  • Premisecitation

    Within 2 weeks of their generation, new neurons begin to take on morphological characteristics of mature granule cells, including a single dendritic tree extending toward the molecular layer and dendritic spines.

    “Within 2 weeks of their generation, new neurons begin to take on the morphological characteristics of mature granule cells with a single dendritic tree extending toward the molecular layer and the formation of dendritic spines, primary sites of excitatory synapses (Zhao et al., 2006) (Figure 1A).”
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  • Premisecitation

    Relatively high numbers of new neurons have been reported in the adult human hippocampus.

    “Relatively high numbers of new neurons have also been reported in the adult human hippocampus (Boldrini et al., 2018; Eriksson et al., 1998; Knoth et al., 2010; Spalding et al., 2013).”
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  • Premisecitation

    Mossy fibers from new granule cells begin to form synapses with excitatory pyramidal cells in CA3 and CA2 and with hilar mossy cells by approximately 2-3 weeks post-mitosis.

    “Mossy fibers from new granule cells begin to form synapses with excitatory pyramidal cells in the CA3 and CA2 subregions (Gu et al., 2012; Llorens-Martín et al., 2015; Toni et al., 2008) as well as with hilar mossy cells (Toni et al., 2008) by approximately 2–3 weeks post-mitosis (Figure 1B).”
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    Premisecitation

    For some time after action potential capability emerges, new granule cells exhibit excitatory instead of inhibitory responses to typically inhibitory neurotransmitter GABA, suggesting they are more likely to fire than mature granule cells.

    “For some time thereafter, new granule cells exhibit excitatory instead of inhibitory responses to typically inhibitory neurotransmitter GABA (Chancey et al., 2013), suggesting that these cells are more likely to fire than mature granule cells, which are strongly inhibited (Amaral et al., 2007; Pelkey et al., 2017).”
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    Premisenone given

    In the hippocampus, adult neurogenesis produces one type of neuron - the dentate gyrus granule cell.

    “In the hippocampus, adult neurogenesis produces one type of neuron – the dentate gyrus granule cell.”
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    Interpretationcitation

    Adult neurogenesis exists in a large number of species, ranging from rodents to monkeys, strongly suggesting it is common to most mammalian species.

    “Evidence that adult neurogenesis exists for a large number of species, ranging from rodents (Jessberger and Gage, 2014; Snyder et al., 2009a) to monkeys (Gould et al., 1998, 1999), strongly suggests that this phenomenon is common to most mammalian species.”
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    • cites Snyder et al., 2009a

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    Interpretationreasoning

    The majority of reports provide positive evidence for adult neurogenesis in the human hippocampus, suggesting that studying this process in rodents is likely relevant to understanding human brain plasticity.

    “A few studies contradict these findings (Cipriani et al., 2018; Sorrells et al., 2018), but the majority of reports provide positive evidence for adult neurogenesis in the hippocampus of humans, suggesting that studying this process in rodents is likely relevant to understanding human brain plasticity.”
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    Interpretationcitation

    Pharmacological blockade of adult neurogenesis rescues the deleterious behavioral effects induced by antidepressant treatment, strongly suggesting that in this case the new neurons impaired hippocampal function.

    “Pharmacological blockade of adult neurogenesis rescued the deleterious behavioral effects induced by antidepressant treatment strongly suggesting that in this case, the new neurons impaired hippocampal function (Alves et al., 2017).”
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    • Rests on an assumption: Manipulations used to reduce adult neurogenesis (transgenic, pharmacological, or focal x-irradiation approaches) affect hippocampal function specifically through loss of new neurons rather than through off-target effects.

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    Premisecitation

    Stress inhibits adult neurogenesis by suppressing the proliferation of radial stem cells and amplifying progenitors, leading to a reduction in neuroblasts.

    “Stress seems to inhibit adult neurogenesis by having a suppressive action on the proliferation of radial stem cells and amplifying progenitors, leading to a reduction in neuroblasts (Dagytė et al., 2009; Mirescu et al., 2004; Opendak et al., 2016) (Table 1).”
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    Premisecitation

    Contradictory studies have found either no effect of reduced neurogenesis on hippocampal cognition or only on certain types of hippocampal cognitive tests, and one study found that absence of new neurons improves cognitive function.

    “On the other hand, contradictory studies have found either no effect of reduced neurogenesis on hippocampal cognition (Groves et al., 2013; Saxe et al., 2006; Shors et al., 2002) or only on certain types of hippocampal cognitive tests (Shors et al., 2002). One study has even found that the absence of new neurons improves cognitive function (Saxe et al., 2007).”
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    Premisecitation

    Seizures induce faster maturation of new granule neurons including early and more extensive mossy fiber sprouting and dendritic outgrowth as well as aberrant basal dendritic trees extending into the hilus.

    “In fact, seizures induce faster maturation of new granule neurons including early and more extensive mossy fiber sprouting and dendritic outgrowth as well as aberrant basal dendritic trees extending into the hilus, which receive recurrent excitatory drive from mossy fibers (Overstreet-Wadiche et al., 2006; Shapiro and Ribak, 2006) (Table 1).”
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    Premisecitation

    Adult neurogenesis in the hippocampus is necessary for stress-induced social avoidance and social cognition.

    “Adult neurogenesis in the hippocampus has been shown to be necessary for stress-induced social avoidance (Lagace et al., 2010), as well as in social cognition (Garrett et al., 2015) (Figure 1C).”
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    • Rests on an assumption: Manipulations used to reduce adult neurogenesis (transgenic, pharmacological, or focal x-irradiation approaches) affect hippocampal function specifically through loss of new neurons rather than through off-target effects.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Functionally relevant aspects of new neuron connectivity likely involve not only connections with other neurons, but also associations with glial cells and the ECM.

    “As introduced above, functionally relevant aspects of new neuron connectivity likely involve not only connections with other neurons, but also associations with glial cells and the ECM.”
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    Premisecitation

    Physical exercise enhances the survival of new cells, increases the development of their dendrites, and increases the complexity of both their afferent and efferent connections.

    “After these new cells are produced and start down the path toward neuronal differentiation, physical exercise enhances their survival, as it increases the development of their dendrites, and the complexity of both their afferent and efferent connections (Ambrogini et al., 2013; Gonçalves et al., 2016b; Llorens-Martín et al., 2015; Snyder et al., 2009b; Zhao et al., 2015) (Table 1).”
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    Interpretationreasoning

    Damage-induced adult neurogenesis may cause abnormal synaptic connectivity.

    “Since integration of new granule neurons into the dentate gyrus unavoidably modifies the existing synaptic circuitry, one possible interpretation of these paradoxical findings is that damage-induced adult neurogenesis causes abnormal synaptic connectivity.”
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    Interpretationreasoning

    Increased numbers of new neurons are associated with improved hippocampal function, while decreased numbers of new neurons are associated with deficient hippocampal function.

    “Taken together, this evidence suggests that increased numbers of new neurons are associated with improved hippocampal function, while decreased numbers of new neurons are associated with deficient hippocampal function.”
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    Premisecitation

    Physical exercise improves performance on hippocampus-dependent cognitive tasks and reduces anxiety-like behaviors.

    “Indeed, numerous studies have shown that physical exercise improves performance on hippocampus-dependent cognitive tasks (reviewed in Vivar et al., 2013) and reduces anxiety-like behaviors (Schoenfeld et al., 2013).”
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    Premisecitation

    The dorsal hippocampus supports spatial navigation learning and memory, and the ventral hippocampus is important for anxiety and stress regulation.

    “Studies have shown that different parts of the hippocampus serve these different functions, with the dorsal hippocampus supporting spatial navigation learning and memory, and the ventral hippocampus as important for anxiety and stress regulation (Fanselow and Dong, 2010; Kheirbek et al., 2013).”
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    Premisecitation

    Inhibiting adult neurogenesis reduces the frequency of chronic seizures along with seizure-related cognitive decline as well as stroke-induced cognitive decline.

    “In fact, inhibiting adult neurogenesis reduces the frequency of chronic seizures along with seizure-related cognitive decline (Cho et al., 2015) as well as stroke-induced cognitive decline (Cuartero et al., 2019).”
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    Premisecitation

    Brain injury models such as stroke, seizure, and blunt trauma all increase the rate of adult neurogenesis, yet each of these conditions is associated with reduced cognitive function.

    “Brain injury models, such as stroke, seizure, and blunt trauma, all increase the rate of adult neurogenesis (Table 1), yet each of these conditions is associated with reduced cognitive function (Cuartero et al., 2019; Parent and Lowenstein, 2002; Sun et al., 2015).”
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    Premisecitation

    Elimination or optogenetic silencing of adult-born neurons impairs pattern separation-like behaviors, while transgenic increases in adult neurogenesis enhance the ability of mice to distinguish between highly similar contexts.

    “Elimination or optogenetic silencing of adult-born neurons impairs pattern separation-like behaviors (Clelland et al., 2009; Danielson et al., 2016), while transgenic increases in adult neurogenesis enhance the ability of mice to distinguish between highly similar contexts (Sahay et al., 2011).”
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    • Rests on an assumption: Manipulations used to reduce adult neurogenesis (transgenic, pharmacological, or focal x-irradiation approaches) affect hippocampal function specifically through loss of new neurons rather than through off-target effects.

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    Premisecitation

    Treatment with the antidepressant fluoxetine results in an overproduction of new neurons in the adult hippocampus, associated with cognitive decline, increased susceptibility to stress-induced depression, and excessive anxiety.

    “Treatment with the antidepressant fluoxetine resulted in an overproduction of new neurons in the adult hippocampus (Alves et al., 2017) (Table 1). This effect, which at first glance appeared to be beneficial, was surprisingly associated with cognitive decline, as well as increased susceptibility to stress-induced depression and excessive anxiety (Alves et al., 2017).”
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    Premisecitation

    The general suppressive effects of stress on adult neurogenesis can be largely attributed to the catabolic actions of glucocorticoids, and the reduction in new neuron formation has been associated with impaired cognitive function.

    “The general suppressive effects of stress on adult neurogenesis can be largely attributed to the catabolic actions of glucocorticoids and the reduction in new neuron formation has been associated with impaired cognitive function (Bondi et al., 2008; Burgado et al., 2014).”
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    Interpretationreasoning

    While reports from direct manipulations of adult neurogenesis often lack consistent results, the majority of studies suggest that new neurons are involved in some aspect of hippocampal-related cognition.

    “While reports from direct manipulations of adult neurogenesis often lack consistent results, the majority of studies suggest that new neurons are involved in some aspect of hippocampal-related cognition.”
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    Premisecitation

    Microglia release factors such as TNF-α or IL-1β, both of which influence synaptic plasticity.

    “releasing factors such as TNF-α or IL-1β, both of which influence synaptic plasticity (Prieto et al., 2018; Stellwagen and Malenka, 2006)”
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    Premisecitation

    Running increases the ratio of inhibitory interneuron versus excitatory mossy cell innervation onto new granule neurons and enhances the number of new axon fibers projecting to the CA3 and CA2 subregions.

    “Using viral-based methods, running has been found to increase the ratio of inhibitory interneuron versus excitatory mossy cell innervation onto new granule neurons (Sah et al., 2017; Vivar et al., 2016) as well as to enhance the number of new axon fibers projecting to the CA3 and CA2 subregions (Llorens-Martín et al., 2015).”
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    Premisecitation

    PNNs are lattice-like structures that form around the cell body and proximal dendrites of certain types of neurons and have been implicated in synaptic stabilization in the adult brain.

    “PNNs are lattice-like structures that form around the cell body and proximal dendrites of certain types of neurons (van ‘t Spijker and Kwok, 2017) and have been implicated in synaptic stabilization in the adult brain (Lensjø et al., 2017a).”
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    Premisecitation

    In the developing brain, peak synaptogenesis coincides with the differentiation and maturation of astrocytes.

    “In the developing brain, peak synaptogenesis coincides with the differentiation and maturation of astrocytes (reviewed in Chung et al., 2015).”
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    Interpretationnone given

    Accumulating evidence suggests a role for the ECM in adult neurogenesis, as well as synaptogenesis, and synaptic signaling.

    “Accumulating evidence suggests a role for the ECM in adult neurogenesis, as well as synaptogenesis, and synaptic signaling.”
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    The extent to which astrocytes and microglia influence functional connectivity of new neurons remains incompletely explored.

    “but the extent to which these cells influence functional connectivity of new neurons remains incompletely explored.”
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    Premisecitation

    Astrocytes within the adult hippocampus influence stem cell proliferation, their commitment to a neuronal phenotype, and their survival.

    “Astrocytes within the adult hippocampus influence stem cell proliferation, their commitment to a neuronal phenotype, and their survival (Song et al., 2002), raising the possibility that there are distinct properties of astrocytes in the hippocampus that promote adult neurogenesis (Figure 2A).”
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    Premisecitation

    Regulation of synaptic connectivity involves at least four main cellular/molecular components: the presynaptic neuron, postsynaptic neuron, glia, and the ECM, which together make up the tetrapartite synapse.

    “Regulation of synaptic connectivity involves at least four main cellular/molecular components: the presynaptic neuron, postsynaptic neuron, glia, and the ECM, which together make up the “tetrapartite synapse” (Dityatev and Rusakov, 2011).”
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    Premisecitation

    Microglia closely monitor neural activity and regulate synaptic plasticity.

    “Microglia also closely monitor neural activity and regulate synaptic plasticity.”
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    Premisecitation

    Genetic disruption of Cx3cr1 decreases the number of new neurons, supporting the importance of microglia-neuron communication in regulating adult neurogenesis.

    “Genetic disruption of Cx3cr1 decreases the number of new neurons (Bachstetter et al., 2011) supporting the importance of microglia-neuron communication in regulating adult neurogenesis.”
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    Premisecitation

    Immune-deficient mice have impaired adult neurogenesis even when housed in environmentally enriched conditions, suggesting that immune molecules, potentially originating from microglia, are necessary for adult neurogenesis.

    “Immune-deficient mice have impaired adult neurogenesis, even when housed in environmentally enriched conditions which typically increase stem cell proliferation, suggesting that immune molecules, potentially originating from microglia, are necessary for adult neurogenesis (Ziv et al., 2006).”
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    Premisecitation

    Environmental enrichment-induced increases in adult neurogenesis are associated with increased synthesis of chondroitin sulfate proteoglycans, which is prevented by chondroitin sulfate proteoglycan synthesis disruption.

    “Environmental enrichment-induced increases in adult neurogenesis are associated with increased synthesis of chondroitin sulfate proteoglycans, which is prevented by chondroitin sulfate proteoglycan synthesis disruption (Yamada et al., 2018).”
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    Premisecitation

    Chondroitin sulfate proteoglycans surround new neurons in the hippocampus and are important for the production and differentiation of new neurons in adulthood.

    “Chondroitin sulfate proteoglycans, structural ECM components, are known to surround new neurons in the hippocampus, and recent work has shown that this molecule is important for the production and differentiation of new neurons in adulthood (Yamada et al., 2018).”
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    Premisecitation

    Depletion of chondroitin sulfate proteoglycans in the hippocampus decreases new neuron formation and dendritic tree maturation, and produces cognitive impairment.

    “Depletion of chondroitin sulfate proteoglycans in the hippocampus decreases new neuron formation and dendritic tree maturation, and produces cognitive impairment (Figure 3A).”
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    Premisecitation

    PNNs are specialized extracellular structures composed of tenascin-R, hyaluronan, chondroitin sulfate proteoglycans, and link proteins, which play important roles in brain plasticity during development and in adulthood.

    “PNNs are specialized extracellular structures composed of tenascin-R, hyaluronan, chondroitin sulfate proteoglycans, and link proteins (Figure 3C), which play important roles in brain plasticity during development and in adulthood (Sorg et al., 2016).”
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    Premisecitation

    Reelin enhances hippocampal synaptic plasticity by altering the composition of NMDA receptor subunits and promoting surface clustering of AMPA receptors.

    “Reelin is also known to enhance hippocampal synaptic plasticity (Pujadas et al., 2010; Weeber et al., 2002) by altering the composition of NMDA receptor subunits and promoting surface clustering of AMPA receptors (Qiu et al., 2006) (Figure 3B).”
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    Interpretationreasoning

    The ECM may spatially restrict microglial and astrocytic processes from invading the perisynaptic space, thus ECM remodeling may prompt invasion of glial cells, which in turn may regulate synaptic signaling.

    “For instance, the ECM may spatially restrict microglial and astrocytic processes from invading the perisynaptic space, thus ECM remodeling may prompt invasion of glial cells, which in turn may regulate synaptic signaling.”
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    Interpretationnone given

    In general, PNNs restrain plasticity and promote synaptic stabilization in the adult brain.

    “In general, PNNs restrain plasticity and promote synaptic stabilization in the adult brain.”
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    Premisecitation

    In the developing and adult hippocampus, tenascin-R deficiency reduces the number of proliferating stem cells, while increasing the number of cells committed to a neuronal phenotype.

    “In the developing and adult hippocampus, tenascin-R deficiency reduces the number of proliferating stem cells, while increasing the number of cells committed to a neuronal phenotype (Xu et al., 2014).”
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    Premisecitation

    Activation of PV+ interneurons promotes new neuron cell survival while suppression of PV+ interneuron activity reduces new neuron cell survival.

    “Since activation of PV+ interneurons has been shown to promote new neuron cell survival while suppression of PV+ interneuron activity reduces new neuron cell survival (Song et al., 2013)”
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    Premisecitation

    Reelin plays a critical role in neuronal migration and synaptic plasticity.

    “has been shown to play a critical role in neuronal migration and synaptic plasticity (reviewed in Lee and D’Arcangelo, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lee and D’Arcangelo, 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tenascins are a critical component of PNNs, which surround many of the neurons that are postsynaptic to adult-generated granule cells.

    “Studies suggest that tenascins are a critical component of PNNs (Suttkus et al., 2014), which surround many of the neurons that are postsynaptic to adult-generated granule cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Suttkus et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the adult mouse hippocampus, reelin deficiency reduces neurogenesis, while reelin overexpression increases neurogenesis.

    “In the adult mouse hippocampus, reelin deficiency reduces neurogenesis (Won et al., 2006), while reelin overexpression increases neurogenesis (Pujadas et al., 2010) (Figure 3A).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Won et al., 2006 source

      Not checked in the free run.

    • cites Pujadas et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tenascin-R knockout mice have altered synaptic plasticity in the hippocampus, including impaired LTP and increased basal excitatory transmission.

    “Several studies have shown that tenascin-R knockout mice have altered synaptic plasticity in the hippocampus, including impaired LTP and increased basal excitatory transmission (Bukalo et al., 2001; Gurevicius et al., 2004; Saghatelyan et al., 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bukalo et al., 2001 source

      Not checked in the free run.

    • cites Gurevicius et al., 2004 source

      Not checked in the free run.

    • cites Saghatelyan et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tenascin-R is important for new neuron production and synaptic plasticity in the adult hippocampus.

    “Tenascin-R, an ECM glycoprotein, is also important for new neuron production and synaptic plasticity in the adult hippocampus.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Liao et al., 2008 source

      Not checked in the free run.

    • cites Xu et al., 2014

      Not checked in the free run.

    • cites Bukalo et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of reelin accelerates dendritic development of adult-born neurons and increases the number of synaptic contacts in the dentate gyrus, whereas the absence of reelin signaling reduces dendritic tree complexity on new granule neurons.

    “Overexpression of reelin accelerates dendritic development of adult-born neurons and increases the number of synaptic contacts in the dentate gyrus (Pejadas et al., 2010; Teixeira et al., 2012), whereas the absence of reelin signaling reduces dendritic tree complexity on new granule neurons (Teixeira et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pejadas et al., 2010

      Not checked in the free run.

    • cites Teixeira et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The reelin pathway participates in the integration of adult-born neurons into the hippocampal circuitry by regulating spine morphology, spine type, and the number of synaptic connections on new granule neurons as well as the degree of perisynaptic astroglial ensheathment of new granule neuron synapses.

    “The reelin pathway also participates in the integration of adult-born neurons into the hippocampal circuitry by regulating spine morphology, spine type, and the number of synaptic connections on new granule neurons as well as the degree of perisynaptic astroglial ensheathment of new granule neuron synapses (Bosch et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bosch et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice deficient in MMP9 have impaired hippocampal LTP, including at mossy fiber-CA3 synapses, which is restored by adding recombinant active MMP9.

    “Mice deficient in MMP9 have impaired hippocampal LTP, including at mossy fiber-CA3 synapses, which is restored by adding recombinant active MMP9 (Nagy et al., 2006; Weira et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nagy et al., 2006 source

      Not checked in the free run.

    • cites Weira et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Changes in the number of new neurons, which alter the overall excitability of the hippocampus, may then regulate the expression of PNNs at postsynaptic sites.

    “one possibility is that changes in the number of new neurons, which alter the overall excitability of the hippocampus (Ikrar et al., 2013), may then regulate the expression of PNNs at postsynaptic sites.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ikrar et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    PNNs have been relatively uninvestigated in the context of adult neurogenesis.

    “PNNs have been relatively uninvestigated in the context of adult neurogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Physical exercise increases new neuron production and improves behaviors associated with the hippocampus, also stimulates astrocyte growth and reduced microglial reactivity.

    “Physical exercise, which increases new neuron production and improves behaviors associated with the hippocampus, also stimulates astrocyte growth (Brockett et al., 2015; Fahimi et al., 2017) and reduced microglial reactivity (Kohman et al., 2012, 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brockett et al., 2015 source

      Not checked in the free run.

    • cites Fahimi et al., 2017 source

      Not checked in the free run.

    • cites Kohman et al., 2012, 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    PNNs may attract or repel axons of new neurons.

    “while PNNs may attract or repel axons of new neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Stress diminishes adult neurogenesis and impairs hippocampal function, reduces the size and number of astrocytes, and triggers microglial reactivity.

    “Stress, on the other hand, which diminishes adult neurogenesis and impairs hippocampal function, has been shown to reduce the size and number of astrocytes (Czéh et al., 2006; Tynan et al., 2013) as well as trigger microglial reactivity (Kreisel et al., 2014; Llorens-Martín et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Czéh et al., 2006

      Not checked in the free run.

    • cites Tynan et al., 2013 source

      Not checked in the free run.

    • cites Kreisel et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Seizures stimulate adult neurogenesis and impair hippocampal function.

    “For example, seizures stimulate adult neurogenesis and impair hippocampal function.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Shapiro et al., 2008 source

      Not checked in the free run.

    • cites Yang et al., 2010 source

      Not checked in the free run.

    • cites McRae and Porter, 2012 source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    Manipulations used to reduce adult neurogenesis (transgenic, pharmacological, or focal x-irradiation approaches) affect hippocampal function specifically through loss of new neurons rather than through off-target effects.

    “Much of this evidence comes from studies that knockdown or eliminate new neurons in the adult brain using transgenic, pharmacological, or focal x-irradiation approaches.”

  • The paper relies on this without support.

    The connectivity of new neurons in the adult hippocampus is highly relevant to their functional influence.

    “It has become increasingly clear that the connectivity of new neurons in the adult hippocampus is highly relevant to their functional influence.”

  • The paper relies on this without support.

    All components of the synapse, including glia, the ECM, and the presynaptic and postsynaptic neurons must be considered in an effort to elucidate the diverse effects new neurons have on brain function.

    “All components of the synapse, including glia, the ECM, and the presynaptic and postsynaptic neurons must be considered in an effort to elucidate the diverse effects new neurons have on brain function.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Microglia participate in stem cell proliferation and survival through release of trophic factors and anti-inflammatory cytokines.

    “A previous study has reported that microglia participate in stem cell proliferation and survival through their release of important trophic factors and anti-inflammatory cytokines.16”

    From Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression (2022) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Saxe et al. (2006) is cited as finding no cognitive effect, but its listed title reports an impairment

    Minor

    The text places Saxe et al. (2006) among studies finding no effect of reduced neurogenesis on hippocampal cognition. Its reference title instead states that ablation impairs contextual fear conditioning, a test the text itself identifies as hippocampal-dependent cognition.

1 of 1

Cites

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Related

Authors
Cope, E. C., & Gould, E.
Affiliations
Princeton University (US)
Corresponding author
Gould, Elizabeth
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2019-05
Volume
24
Issue
5
Pages
690-705
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2019.03.023
PMC
PMC7961263
OpenAlex
W2942783247
Semantic Scholar
194e87b067e2102bb5954d25a3fad0864c796ea7
Cited by
236
References
205
Citations by year
2026: 16 · 2025: 36 · 2024: 48 · 2023: 41 · 2022: 41 · 2021: 33 · 2020: 17 · 2019: 4
FWCI
2.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (MH117459-01, T32MH065214)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
adult neurogenesis, hippocampus, glia, extracellular matrix, stem/progenitor cells, hippocampal circuitry, learning and memory, social behavior
MeSH terms
Adult, Animals, Astrocytes, Cell Differentiation, Extracellular Matrix, Hippocampus, Humans, Neurons, Oligodendroglia, Microglia, Neurogenesis, Neural Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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