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Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity. Proc Natl Acad Sci USA

Institut National de la Santé et de la Recherche Médicale U862, Neurocentre Magendie, Glia-Neuron Interactions Group, F33077 Bordeaux, France.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2011; 108(16):6644-9. DOI: 10.1073/pnas.1016928108
Source: PubMed

ABSTRACT Adult neurogenesis is a process by which the brain produces new neurons once development has ceased. Adult hippocampal neurogenesis has been linked to the relational processing of spatial information, a role attributed to the contribution of newborn neurons to long-term potentiation (LTP). However, whether newborn neurons also influence long-term depression (LTD), and how synaptic transmission and plasticity are affected as they incorporate their network, remain to be determined. To address these issues, we took advantage of a genetic model in which a majority of adult-born neurons can be selectively ablated in the dentate gyrus (DG) and, most importantly, in which neurogenesis can be restored on demand. Using electrophysiological recordings, we show that selective reduction of adult-born neurons impairs synaptic transmission at medial perforant pathway synapses onto DG granule cells. Furthermore, LTP and LTD are largely compromised at these synapses, probably as a result of an increased induction threshold. Whereas the deficits in synaptic transmission and plasticity are completely rescued by restoring neurogenesis, these synapses regain their ability to express LTP much faster than their ability to express LTD. These results demonstrate that both LTP and LTD are influenced by adult neurogenesis. They also indicate that as newborn neurons integrate their network, the ability to express bidirectional synaptic plasticity is largely improved at these synapses. These findings establish that adult neurogenesis is an important process for synaptic transmission and bidirectional plasticity in the DG, accounting for its role in efficiently integrating novel incoming information and in forming new memories.

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Available from: Federico Massa, Aug 28, 2015
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    • "Cognitive deficits constitute a critical pathological feature that is difficult to treat in many psychiatric and neurological disorders, which have been suggested to be associated with impaired adult hippocampal neurogenesis (Leuner et al., 2006; Massa et al., 2011; King et al., 2014). Neurogenesis involves neural precursor cell (NPC) proliferation and differentiation into neurons, a process that has been linked to hippocampal-dependent cognitive processes (Kempermann, 2002; van Praag et al., 2005; Leuner et al., 2006; Deng et al., 2010; Massa et al., 2011). The potential coexistence of impairments in cognitive processes and hippocampal neurogenesis, for example in Alzheimer's disease (Mu and Gage, 2011), Fragile X syndrome (Guo et al., 2012), and mood disorders (Jacobs et al., 2000), raises the possibility that the two are linked. "
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    ABSTRACT: Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3. NPC proliferation was ∼40% deficient in both male and female GSK3 knockin mice compared with WT mice. Environmental enrichment (EE) increased NPC proliferation in male, but not female, GSK3 knockin mice and WT mice. Male and female GSK3 knockin mice exhibited impairments in novel object recognition, temporal order memory, and coordinate spatial processing compared with gender-matched WT mice. EE restored impaired novel object recognition and temporal ordering in both sexes of GSK3 knockin mice, indicating that this repair was not dependent on NPC proliferation, which was not increased by EE in female GSK3 knockin mice. Acute 1 h pretreatment with the GSK3 inhibitor TDZD-8 also improved novel object recognition and temporal ordering in male and female GSK3 knockin mice. These findings demonstrate that hyperactive GSK3 is sufficient to impair adult hippocampal NPC proliferation and to impair performance in three cognitive tasks in both male and female mice, but these changes in NPC proliferation do not directly regulate novel object recognition and temporal ordering tasks.
    Frontiers in Behavioral Neuroscience 03/2015; Epub ahead of print. DOI:10.3389/fnbeh.2015.00055 · 4.16 Impact Factor
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    • "Young (1.5–2 months old) newborn neurons were also shown to be preferentially activated during memory recall in a water maze task, compared to mature neurons, as determined by colabeling of BrdU with immediate early genes such as c- Fos and Arc, in which expression correlates with neuronal firing [48]. Nonetheless, it has only been in the last few years that loss-of-function and gain-of-function approaches with inducible transgenic mice were able to confirm that adult hippocampal neurogenesis is necessary for synaptic transmission and plasticity, including the induction of longterm potentiation (LTP) and long-term depression [49], as well as trace learning in conditioned protocols [50], memory retention in spatial learning tasks [51] [52], and encoding of overlapping input patterns, that is, pattern separation [53]. Adult hippocampal neurogenesis and its functional implications for learning and memory are however influenced negatively by a variety of conditions that are commonly associated with microglial activation and inflammation in the brain, such as chronic stress, aging, and neurodegenerative diseases, as we will review herein. "
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    ABSTRACT: Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.
    Neural Plasticity 03/2014; 2014(2):610343. DOI:10.1155/2014/610343 · 3.60 Impact Factor
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    • "Differently from more mature DG neurons, the newly-generated cells integrated in the DG 30–45 days after mitosis are indeed insensitive to GABAergic inhibition. In rodents aCSF-LTP is absent when neurogenesis is chemically, physically or genetically reduced, whereas it is enhanced when neurogenesis is increased [53], [59], [61], [68], [69]. We found that aCSF-LTP was similar in all groups except for the TMT+NPY group, in which it was significantly enhanced, thus supporting the functional integration of newly-generated granule cells in the DG network of TMT+NPY-treated animals. "
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    PLoS ONE 02/2014; 9(2):e88294. DOI:10.1371/journal.pone.0088294 · 3.23 Impact Factor
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