Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats

Pertusa, Marı́a; García-Matas, Silvia; Mammeri, Hamid; Adell, Albert; Rodrigo, T.; Mallet, Jacques; Cristòfol, Rosa; Sarkis, Chamsy; Sanfeliu, Coral

doi:10.1016/j.neurobiolaging.2007.02.026

Cited by 101 publications

(76 citation statements)

References 128 publications

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“…Furthermore, expression of the Gdnf transgene in astrocytes has been reported to improve cognitive deficits in aged rats (Pertusa et al, 2008). Our findings suggest the existence of an underlying mechanism that might explain these observations and predict cognitive impairments in mouse strains lacking hippocampal GFRα1.…”

Section: Hippocampal Dendrite Growth Is Induced By Gdnf and Gfrα1supporting

confidence: 56%

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

et al. 2016

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The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain-and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1-induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.

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Section: Hippocampal Dendrite Growth Is Induced By Gdnf and Gfrα1supporting

confidence: 56%

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

et al. 2016

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“…Glial cells such as astrocytes are emerging as important regulators of synaptic plasticity and cognition and may play an important role in hippocampus-dependent learning and memory (24). It is yet to be determined whether the effects of TLR3 signaling on working memory are mediated solely by changes in neurons or whether there is a also a role for glial TLR3 signaling.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis

Okun

Griffioen

Barak

et al. 2010

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

181

149

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Toll-like receptors (TLRs) are innate immune receptors that have recently emerged as regulators of neuronal survival and developmental neuroplasticity. Adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdalarelated behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention.oll-like receptors (TLRs) are innate immunity-related receptors that sense pathogen-associated molecular patterns (1) as well as tissue damage-associated molecular patterns (2). Although TLRs are abundant in the immune system, some TLRs are also expressed in central nervous system (CNS) cells where they mediate infection and injury responses (3). For example, activation of TLR4 by bacterial lipopolysaccharide up-regulates proinflammatory cytokine and chemokine production in microglia, and this TLR4 action on microglia is critical for the recruitment of circulating leukocytes into the brain (4). Neurons also express TLRs, and it was recently reported that activation of TLR2 and TLR4 in cortical neurons increases their vulnerability to ischemic injury (5). TLRs mediate innate immune responses, in part, through nuclear factor-κB (NF-κB) and IFN regulatory factor (IRF)-dependent pathways (3). Recent findings suggest that some TLRs modulate neural plasticity. For example, TLR3 inhibits neural progenitor cell (NPC) proliferation in the embryonic mouse telencephalon (6) and inhibits axonal growth in DRG neurons (7). More recently, Peltier et al. (8) found that human neurons are capable of a functional TLR3 signaling mechanism. Here we provide evidence that TLR3 signaling negatively regulates hippocampus-dependent learning and memory and suppresses hippocampal neurogenesis and AMPA receptor expression in CA1 neurons. We further show that constitutive physiological TLR3 signaling suppresses ERK and CREB activities, suggesting a mechanism whereby TLR3 regulates hippocampal neurogenesis and behavioral plasticity. Results TLR3 Deficiency Enhances Hippocampus-Dependent, but ImpairsAmygdala-Dependent, Learning and Memory. To determine whether TLR3 affects cognitive function, we compared spatial memo...

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“…GDNF improves cognitive function (5,6) while also inhibiting drug-induced dependence (7). These results suggest that GDNF plays a crucial role in not only neuronal development but also neuronal and glial plasticity in higher-ordered brain function.…”

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confidence: 81%

Tricyclic Antidepressant Amitriptyline Activates Fibroblast Growth Factor Receptor Signaling in Glial Cells

Hisaoka

Tsuchioka

Yano

et al. 2011

Journal of Biological Chemistry

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Brain imaging studies have revealed that both the hippocampus and prefrontal cortex undergo selective volume reduction in major depressive disorder (MDD).2 One of the most consistent findings, associated with the volume reduction, in postmortem studies of MDD is a decrease in the density and number of glia in several cortical areas (1). The decreases in glial density are accompanied by a reduction of astrocytic markers, such as glial fibrillary acidic protein and glutamine synthetase (1, 2), thus suggesting that glia, especially astrocytes might be involved in the pathophysiology of MDD.One of the major role of astrocytes is the production of neurotrophic factors, such as nerve growth factor (NGF), brainderived neurotrophic factor, fibroblast growth factor (FGF), and glial cell line-derived neurotrophic factor (GDNF), which support neurogenesis, gliogenesis, development, plasticity, and survival (3).GDNF, a member of the transforming growth factor-␤ superfamily, was originally purified from a rat glial cell line supernatant as a trophic factor for midbrain dopamine neurons and was later found to have pronounced effects on other neuronal populations and glia (4). GDNF improves cognitive function (5, 6) while also inhibiting drug-induced dependence (7). These results suggest that GDNF plays a crucial role in not only neuronal development but also neuronal and glial plasticity in higher-ordered brain function.A growing body of evidence suggests that GDNF as well as brain-derived neurotrophic factor is involved in the pathophysiology of . GDNF has been shown to decrease in the peripheral blood of patients with MDD (8). In addition, the decreased blood level of GDNF in MDD has been reported to increase after antidepressant treatment (13). We have also previously shown that antidepressants increase the GDNF production in C6 glioma cells (C6 cells), rat astrocytes, and normal human astrocytes (NHA) (14,15). Treatment with antidepressants alters the GDNF levels in rodents in vivo and glial cell culture in vitro (16 -18). These findings suggest that an increase of GDNF production may be involved in the therapeutic effect *

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Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats

Cited by 101 publications

References 128 publications

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis

Tricyclic Antidepressant Amitriptyline Activates Fibroblast Growth Factor Receptor Signaling in Glial Cells

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