Non-Cell-Autonomous Regulation of GABAergic Neuron Development by Neurotrophins and the p75 Receptor

Lin, Pao‐Yen; Hinterneder, Jeanine M.; Rollor, Sarah R.; Birren, Susan J.

doi:10.1523/jneurosci.3302-07.2007

Cited by 22 publications

(30 citation statements)

References 53 publications

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“…TNFα is a hallmark of acute and chronic neuroinflammation and has emerged as an important candidate for mediating non-cell-autonomous effects in these conditions (47). p75 NTR expressed by cholinergic neurons is required for production of an unknown factor that facilitates GABAergic neuron development (48), and p75 NTR expressed on Müller glial cells mediates light-induced photoreceptor death via a non-cell-autonomous pathway (9). The potential role of TNFα downstream of these p75 NTR -dependent events will be an interesting topic for future work.…”

Section: Resultsmentioning

confidence: 99%

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

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

111

100

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Neurotrophin binding to the p75 neurotrophin receptor (p75 NTR ) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75 NTR -dependent signaling mechanism. Expression of p75 NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cellautonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75 NTR , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.T he four mammalian neurotrophins comprise a family of related secreted factors that are required for differentiation, survival, development, and death of specific populations of neurons and nonneuronal cells. Neurotrophins are produced as proforms of ∼240 amino acids that are cleaved by furins and proconvertases to yield products of ∼120 amino acids. Recent studies have indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can be secreted as proforms in the central nervous system (CNS) (1-3) and demonstrated that proneurotrophins can function as potent apoptosis-inducing ligands both in vitro and in vivo (4). However, the precise mechanisms by which proneurotrophins lead to neuronal death are poorly defined.The biological effects of neurotrophins are mediated by binding to TrkA, TrkB, and TrkC receptor tyrosine kinases and to the p75 neurotrophin receptor (p75 NTR ). Trk receptors respond preferentially to mature neurotrophins whereas proneurotrophins exert their apoptotic effect via a receptor complex that contains p75 NTR and sortilin (5). The precise signaling cascades evoked by occupancy of the p75 NTR -sortilin complex remain to be elucidated, but several lines of evidence indicate that NRIF and NRAGE adaptor proteins play key roles in death signaling cascades evoked by p75 NTR (6, 7).Previous studies have shown that neurotrophins induce cell death via p75 NTR during early retinal development (8). p75 NTR has also been implicated in light-induced photoreceptor death in adult rodents in vivo (9) and a proNGF-p75 NTR link has been proposed to facilitate apoptosis in a retinal cell line (10). Here, we investigate the role of proNGF in the adult retina and demonstrate that proNGF promotes death of retinal ganglion cells (RGCs) in vivo. Importantly, proNGF-induced RGC loss is indirect and requires the p75 NTRdependent production of tumor necrosis...

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Section: Resultsmentioning

confidence: 99%

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

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

111

100

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“…Actually, BDNF increases the differentiation of hippocampal and neocortical inhibitory interneurons, promotes a GABAergic phenotype in hippocampal granule cells (12,28), and enhances the expression of GAD67 in primary hippocampal cultures obtained from adult mice (1). In addition, BDNF stimulates neurogenesis in the SGZ or SVZ regions following cerebral ischemia (7,40).…”

Section: Discussionmentioning

confidence: 99%

New GABAergic Neurogenesis in the Hippocampal CA1 Region of a Gerbil Model of Long‐Term Survival after Transient Cerebral Ischemic Injury

et al. 2015

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We investigated the probability of newly generated neurons that could survive and mature in the ischemic hippocampal CA1 region (CA1) of a gerbil model of transient cerebral ischemia. Neuronal death was shown in the stratum pyramidale (SP) from 4 days post-ischemia, and a significant increase in NeuN-positive ((+) ) neurons was found in the SP at 180 days post-ischemia. 5-Bromo-2-deoxyuridine (BrdU)(+) cells were co-stained with NeuN and glutamic decarboxylase 67 (GAD67). Brain-derived neurotrophic factor (BDNF) immunoreactivity and protein level was shown in nonpyramidal cells from 4 days post-ischemia, and the immunoreactivity was strong at 30 days post-ischemia and not significantly changed until 180 days post-ischemia. Furthermore, TrkB immunoreactivity was co-stained with GAD67 when we examined at 180 days post-ischemia. Myelin basic protein (MBP)(+) nerve fibers were reduced at 4 days post-ischemia and maintained until 60 days post-ischemia, and MBP immunoreactivity and levels were significantly increased at 180 days post-ischemia. In the passive avoidance test, cognitive dysfunction was improved at 180 days post-ischemia. These results suggest that the differentiation of neural progenitor cells into new GABAergic neurons may be promoted via BDNF in the ischemic CA1 and that the neurogenesis may partially mediate the recovery of cognitive impairments via increasing myelinated nerve fibers.

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“…The cellular basis for such cognitive deficits observed in trkA knockdown rats that received proNGF Ab is not entirely clear and remains somewhat speculative. The development of BF GABAergic neurons is regulated by proNGF-p75 signaling via a non-cell autonomous mechanism (Lin et al, 2007) or potentially through a cell autonomous mechanism (Formaggio et al, 2011). Moreover, these non-cholinergic corticopetal neurons are known to mediate the executive aspects of attention (Burk and Sarter, 2001).…”

Section: Discussionmentioning

confidence: 99%

Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system

Yegla

Parikh

2014

Neuroscience

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Disruption in nerve growth factor (NGF) signaling via trkA receptors compromises the integrity of the basal forebrain (BF) cholinergic system, yielding cognitive, specifically attentional, impairments in Alzheimer’s disease (AD). Although normal aging is considered a risk factor for AD, the mechanisms underlying the selective vulnerability of the aging cholinergic system to trkA disruption is not clear. The levels of proNGF, a proneurotrophin that possesses higher affinity for p75 receptors, increase in aging. The present study was designed to test the hypothesis that cholinergic and attentional dysfunction in aged rats with reduced BF trkA receptors occurs due to the overactivation of endogenous proNGF signaling. We employed a viral vector that produced trkA shRNA to suppress trkA receptors in the corticopetal cholinergic neurons of aged rats. BF trkA suppression impaired animals’ performance on signal trials in both the sustained attention task (SAT) and the cognitively-taxing distractor version of SAT (dSAT) and these deficits were normalized by chronic intracerebroventricular administration of proNGF antibody. Moreover, depolarization-evoked ACh release and the density of cortical cholinergic fibers were partially restored in these animals. However, SAT/dSAT scores reflecting overall performance did not improve following proNGF blockade in trkA knockdown rats due to impaired performance in non-signal trials. Sustained proNGF blockade alone did not alter baseline attentional performance but produced moderate impairments during challenging conditions. Collectively, our findings indicate that barring proNGF-p75 signaling may exert some beneficial effects on attentional capacities specifically when BF trkA signaling is abrogated. However, endogenous proNGF may also possess neurotrophic effects and blockade of this proneurotrophin may not completely ameliorate attentional impairments in AD and potentially hinder performance during periods of high cognitive load in normal aging.

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Non-Cell-Autonomous Regulation of GABAergic Neuron Development by Neurotrophins and the p75 Receptor

Cited by 22 publications

References 53 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

New GABAergic Neurogenesis in the Hippocampal CA1 Region of a Gerbil Model of Long‐Term Survival after Transient Cerebral Ischemic Injury

Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system

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Non-Cell-Autonomous Regulation of GABAergic Neuron Development by Neurotrophins and the p75 Receptor

Cited by 22 publications

References 53 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

New GABAergic Neurogenesis in the Hippocampal CA1 Region of a Gerbil Model of Long‐Term Survival after Transient Cerebral Ischemic Injury

Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system

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ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway