Bcl2 enhances survival of newborn neurons in the normal and ischemic hippocampus

Sasaki, Tsutomu; Kitagawa, Kazuo; Yagita, Yoshiki; Sugiura, Shiro; Omura-Matsuoka, Emi; Tanaka, Shigeru; Matsushita, Kohji; Okano, Hideyuki; Tsujimoto, Yoshihide; Hori, Masatsugu

doi:10.1002/jnr.21036

Cited by 66 publications

(41 citation statements)

References 20 publications

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“…Bcl-2 plays a protective role against apoptotic and necrotic cell death in response to various stimuli including ischemia (Sasaki et al, 2006;Zhang et al, 2006). It is known that HDACIs increase the expression of Bcl-2 (Chen et al, 1999;Faraco et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

A Critical Time Window for the Survival of Neural Progenitor Cells by HDAC Inhibitors in the Hippocampus

Kim

Yang

Lee

et al. 2011

Molecules and Cells

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*Histone deacetylase inhibitors (HDACIs) that modulate gene expression by inhibiting HDAC enzymes may contribute to the survival of immature hippocampal neurons. However, it remains unknown how and when HDACIs regulate the survival of newly generated immature hippocampal neurons. In the present study, if the treatment of valproic acid (VPA) and sodium butyrate (SBt) in the specific time window during the development of newly generated neurons resulted in the increased survival of bromodeoxyuridine (BrdU)(+) neurons in the dentate gyrus (DG) of hippocampus in mice was investigated. It was found that the number of BrdU(+) cells, the expressions of anti-apoptotic Bcl-2 family members and pCREB [D1] were increased by HDACIs when HDACIs were treated no later than 2-3 weeks after BrdU labeling. This suggests that epigenetic modification within a specific time window is critical for the survival of newborn hippocampal neurons by inhibiting the apoptotic pathway.

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Section: Resultsmentioning

confidence: 99%

A Critical Time Window for the Survival of Neural Progenitor Cells by HDAC Inhibitors in the Hippocampus

Kim

Yang

Lee

et al. 2011

Molecules and Cells

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“…Structurally, bcl2l2 is a member of the bcl2 family, and bcl2 is known to enhance survival of newborn neurons in the hippocampus (26). Similarly, bcl2l2 has been shown to play a role in cell survival in cell lines (27).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Turner

Clinton

Thompson

et al. 2011

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

112

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Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety-and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders. elevated plus maze | gene expression microarray H uman postmortem studies suggest a role for the fibroblast growth factor (FGF) system in the pathophysiology of mood disorders. The expression of several members of the FGF family was altered in the forebrain of patients with major depressive disorder (MDD). Specifically, FGF2 mRNA expression was down-regulated in cortical areas and the hippocampus in MDD compared with controls (1, 2). The hippocampus seems to be particularly affected in MDD (3). A potential role for FGF2 in depression and anxiety disorders was first suggested by pharmacological studies in rodents, which showed that administration of antidepressant and anxiolytic drugs can increase FGF2 expression in the hippocampus (3-6). We then asked whether FGF2 is a modulator of emotionality in rodents and discovered that repeated administration of FGF2 was both antidepressant and anxiolytic (7,8).Using rats selectively bred for differences in novelty-seeking, we found that hippocampal expression of FGF2 mRNA was higher in high responders to novelty (bHRs) than in the low responders to novelty (bLRs). The bHRs have higher FGF2 levels and exhibit less anxiety-like behavior, whereas the bLRs exhibit more anxiety-like behavior. FGF2 seems to be a protective factor against anxiety-like behavior in the adult (7). Th...

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“…10 In brief, sections were treated with 50% formamide and 2ϫ saline-sodium citrate buffer and then incubated in 2N HCl. After a wash, sections were incubated with rat monoclonal anti-BrdU antibody (1:100, Harlan Sera-Laboratory, Loughborough, UK) at 4°C overnight.…”

Section: Bromodeoxyuridine Labeling Protocols and Immunohistochemistrymentioning

confidence: 99%

The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia

Sasaki

Kitagawa

Omura-Matsuoka

et al. 2007

Stroke

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Background and Purpose-Brain ischemia stimulates neurogenesis. However, newborn neurons show a progressive decrease in number over time. Under normal conditions, the cAMP-cAMP responsive element binding protein (CREB) pathway regulates the survival of newborn neurons. Constitutive activation of CREB after brain ischemia also stimulates hippocampal neurogenesis. Thus, activation of cAMP-CREB signaling may provide a promising strategy for enhancing the survival of newborn neurons. We examined whether treatment of mice with the phosphodiesterase-4 inhibitor rolipram enhances hippocampal neurogenesis after ischemia. Methods-Both common carotid arteries in mice were occluded for 12 minutes. Bromodeoxyuridine (BrdU) was used to label proliferating cells. Mice were perfused transcardially with 4% paraformaldehyde, and immunohistochemistry was performed. To evaluate the role of CREB in the survival of newborn neurons after ischemia, intrahippocampal injection of a CRE-decoy oligonucleotide was delivered for 1 week. We examined whether the activation of cAMP-CREB signaling by rolipram enhanced the proliferation and survival of newborn neurons. Results-Phospho-CREB immunostaining was markedly upregulated in immature neurons, decreasing to low levels in mature neurons. The number of BrdU-positive cells 30 days after ischemia was significantly less in the CRE-decoy treatment group than in the vehicle group. Rolipram enhanced the proliferation of newborn cells under physiologic conditions but not under ischemic conditions. Rolipram significantly increased the survival of nascent BrdU-positive neurons, accompanied by an enhancement of phospho-CREB staining and decreased newborn cell death after ischemia. Conclusions-CREB phosphorylation regulates the survival of newborn neurons after ischemia. Chronic pharmacological activation of cAMP-CREB signaling may be therapeutically useful for the enhancement of neurogenesis after ischemia.

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Bcl2 enhances survival of newborn neurons in the normal and ischemic hippocampus

Cited by 66 publications

References 20 publications

A Critical Time Window for the Survival of Neural Progenitor Cells by HDAC Inhibitors in the Hippocampus

A Critical Time Window for the Survival of Neural Progenitor Cells by HDAC Inhibitors in the Hippocampus

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia

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