Increased vulnerability of hippocampal neurons with age in culture: Temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels

Brewer, Lawrence D.; Thibault, Olivier; Staton, J.; Thibault, Véronique; Rogers, Justin T.; Garcı́a-Ramos, Gisela; Kraner, Susan D.; Landfield, Philip W.; Porter, Nada M.

doi:10.1016/j.brainres.2007.03.020

Cited by 85 publications

(92 citation statements)

References 72 publications

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“…23,28,29 In the present study, we observed a delayed vulnerability of Stat5 À/À hippocampal neurons to glutamate. Also, the switch from the early developmental pattern of mostly NR2B-mediated to the mature NR2A þ NR2B-mediated toxicity 23 was delayed in the Stat5-deficient cells. Since the Stat5 pathway is commonly associated with neuronal survival, 6-9,12 a Stat5-mediated toxicity upon glutamate treatment seems unlikely.…”

Section: Discussionsupporting

confidence: 66%

“…Since the vulnerability of hippocampal neurons to glutamate is known to increase with increasing days in vitro due to developmentally regulated changes in the composition of the NMDA receptors from predominantly NR1-NMDA receptor subunit 2B (NR2B) in young to a mixed NR1-NMDA receptor subunit 2A (NR2A) and NR1-NR2B oligomers in more mature neurons, 22,23 we compared the protective effect of NR2B subunit-specific blocker, ifenprodil, against glutamate toxicity in younger and older cultures. Typical to the more immature character of the neurons on DIV9, glutamate toxicity in both Stat5 þ / þ and Stat5 À/À neurons was completely blocked by ifenprodil (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…Glutamate, the main excitatory neurotransmitter in the mammalian brain, is in high concentrations toxic through activation of its receptors and subsequent intracellular Ca 2 þ overload, leading to necrotic cell death. 23,28,29 The vulnerability to glutamate increases with neuronal maturation. 23,28,29 In the present study, we observed a delayed vulnerability of Stat5 À/À hippocampal neurons to glutamate.…”

Section: Discussionmentioning

confidence: 99%

“…23,28,29 The vulnerability to glutamate increases with neuronal maturation. 23,28,29 In the present study, we observed a delayed vulnerability of Stat5 À/À hippocampal neurons to glutamate. Also, the switch from the early developmental pattern of mostly NR2B-mediated to the mature NR2A þ NR2B-mediated toxicity 23 was delayed in the Stat5-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

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Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

et al. 2008

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The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) are activated by the neuroprotective and neurotrophic cytokines, erythropoietin (EPO) and growth hormone (GH). Here, we show a dissociation of the intracellular pathway mediating the protective effect of EPO against glutamate toxicity from that needed for its neurotrophic activity using hippocampal neuronal cultures from Stat5a/b-knockout (Stat5 À/À ) mouse fetuses. Both pretreatment and post-treatment with EPO counteracted glutamate-induced cell death in Stat5 þ / þ and Stat5 À/À neurons. Acute pharmacological inhibition of Janus kinase 2 (JAK2)/Stat signalling had no effect on EPO neuroprotection, whereas inhibition of phosphatidylinositol-3 0 kinase (PI3K)/Akt pathway abolished the protective effect of EPO in both Stat5 þ / þ and Stat5 À/À neurons. GH effectively protected Stat5 þ / þ cells against glutamate toxicity but had no effect in Stat5 À/À neurons or in Stat5 þ / þ neurons treated with JAK2/Stat or PI3K inhibitor. EPO and GH stimulated neurite outgrowth and branching of Stat5 þ / þ neurons by activating PI3K/Akt signalling but had no trophic effect in Stat5 À/À cells. We conclude that in hippocampal neurons, Stat5 is not required for neuroprotection by EPO but is together with Akt essential for its neurotrophic activity. Both Stat5 and Akt are needed for neuroprotective and neurotrophic signalling of GH in neurons. The transcription factors signal transducer and activator of transcription 5a and 5b (Stat5) control cell fate decisions such as differentiation, proliferation and apoptosis. 1 Stat5 mediates cellular response to cytokines, growth factors and hormones. 1 Upon binding to their membrane receptors, growth factors such as erythropoietin (EPO) and growth hormone (GH) activate Janus kinase 2 (JAK2), causing activation of Stat5 by its phosphorylation, dimerization and translocation to the nucleus, where Stat5 induces expression of various antiapoptotic genes. 1 Indicative of an impaired functioning of EPO and GH receptor-associated signalling, Stat5a/b-knockout mice (Stat5 À/À ) are severely anaemic and growth retarded and the vast majority die perinatally. 2 Stat5 is expressed in the developing nervous system. 3,4 Recent studies suggest a role for Stat5 in neuronal migration and axon guidance in the developing brain 3 and a novel therapeutic potential for constitutively active Stat5 in reducing axonal outgrowth defects in spinal muscular atrophy-like motor neurons. 5 Since activation of Stat5 in neurons accompanies the antiapoptotic and neuroprotective effects of EPO in vitro and in vivo, 6-12 Stat5 has been suggested to mediate the protective effects of EPO in neuronal cells. Nevertheless, the molecular mechanisms of EPO receptor (EPOR) activation in neurons are complex, as multiple neuroprotective signalling pathways are activated downstream of EPOR/JAK2. In addition to Stat5, best characterized from these are the phosphatidylinositol-3 0 kinase (PI3K)/ Akt, nuclear factor-kB and Ras/mitogen-activated p...

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Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

et al. 2008

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“…By applying different doses of nimodipine to N9 and BV-2 cultures for 24 h, we were able to detect a dose-dependent loss of cells. Doses were chosen according to the literature (13,24,25). A dose of 1 μM nimodipine did not lead to a significant difference compared with vehicle-treated cells, but in both cell lines a dose of 5 μM significantly reduced the number of microglial cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

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

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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2 + APC + oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.M ultiple sclerosis (MS) is the most prevalent neurological disease of the CNS in young adults and is characterized by inflammation, demyelination, and axonal pathology (1) that result in multiple neurological and cognitive deficits (1-3). Intensive MS research studies have investigated modulating the immune system (4). Common therapeutic strategies are effective in slowing disease progression and attenuating the symptoms, but they cannot cure the disease. The option of preventing neurodegeneration early on would be a valuable addendum to customary treatment (4). Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5, 6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7-9). Current research trials are examining its effects on brain injury, epilepsy, cognitive performance, and behavioral effects (6,7,10,11). Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10, 12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6). So far, nimodipine-mediated effects in the CNS have been claimed to result mainly from the modulation of neuronal activity, and studies on the potential effects of nimodipine on (micro)glia have not yet been conduct...

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N‐methyl‐D‐aspartate‐stimulated ERK1/2 signaling and the transcriptional up‐regulation of plasticity‐related genes are developmentally regulated following in vitro neuronal maturation

Zhou

Moon

Zheng

et al. 2009

J of Neuroscience Research

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The general features of neuroplasticity are developmentally regulated. Although it has been hypothesized that the loss of plasticity in mature neurons may be due to synaptic saturation and functional reduction of NMDA receptors (NMDAR), the molecular mechanisms remain largely unknown. We examined the effects of NMDAR activation and KCl-mediated membrane depolarization on ERK1/2 signaling following in vitro maturation of cultured cortical neurons. Although NMDA stimulated robust increase of intracellular calcium at both DIV (day in vitro) 3 and 14, the activation of ERK1/2 and CREB was impaired at DIV 14. Specifically, the phosphorylation of ERK1/2 was stimulated by both NMDA and KCl at DIV 3. However, at DIV 14, NMDA-, but not KCl-stimulated ERK1/2 and CREB phosphorylation was significantly diminished. Consistently, the NMDA-induced transcription of ERK/CREB-regulated genes Bdnf exon 4, Arc and zif268 was significantly attenuated at DIV 14. Moreover, compared to DIV 3 neurons, the basal level of phosphorylated-ERK1/2 in DIV 14 neurons increased tremendously following maturation, and was more susceptible to dephosphorylation. Blocking calcium channels by nifedipine or NMDAR by APV caused more dramatic ERK dephosphorylation in DIV 14 neurons. We further demonstrate that the loss of plasticity-related signaling is unrelated to NMDA-induced cell death of the DIV 14 neurons. Taken together, these results suggest that the attenuation of certain aspects of neuroplasticity following maturation may be due to the reduction of NMDAR-mediated gene transcription and a saturation of ERK1/2 activity.

show abstract

Increased vulnerability of hippocampal neurons with age in culture: Temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels

Cited by 85 publications

References 72 publications

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

N‐methyl‐D‐aspartate‐stimulated ERK1/2 signaling and the transcriptional up‐regulation of plasticity‐related genes are developmentally regulated following in vitro neuronal maturation

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