Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. ...Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.
Initially characterized for their roles in apoptosis, executioner caspases have emerged as important regulators of an array of cellular activities. This is especially true in the nervous system, ...where sublethal caspase activity has been implicated in axonal pathfinding and branching, axonal degeneration, dendrite pruning, regeneration, long-term depression, and metaplasticity. Here we examine the roles of sublethal executioner caspase activity in nervous system development and maintenance, consider the mechanisms that locally activate and restrain these potential killers, and discuss how their activity be subverted in neurodegenerative disease.
The review by Unsain and Barker examines the emerging roles of sublethal caspase activity in nervous system development and maintenance. They discuss mechanisms that act locally to regulate these potential killers and then consider how they may go awry in neurodegenerative disease.
The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma Na+ and osmolality rise in proportion with salt intake and thus promote release of ...vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit.
•Chronic high salt intake reduces chloride gradient in vasopressin neurons•BDNF-TrkB activation causes KCC2 downregulation and collapse of chloride gradient•High salt intake abolishes baroreceptor inhibition of vasopressin neurons•Circulating vasopressin mediates high blood pressure during high salt intake
High salt consumption is causally linked to hypertension with unclear etiology. Choe et al. show that chronic high salt modifies a hypothalamic circuit, leading to excessive release of the antidiuretic hormone vasopressin. The resulting peripheral vasoconstriction increases blood pressure.
Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of ...evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.
Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factor α (TNFα) signaling has been linked to RGC damage, however, the mechanism by which ...TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca(2+)-permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma.
Tumor necrosis factor α (TNFα) has been implicated in retinal ganglion cell (RGC) death, but how TNFα exerts this effect is poorly understood. We report that ocular hypertension, a major risk factor in glaucoma, upregulates TNFα production by Müller cells and microglia. Inhibition of soluble TNFα using a dominant-negative strategy effectively promotes RGC survival. We find that TNFα stimulates the expression of calcium-permeable AMPA receptors (CP-AMPAR) in RGCs, a response that does not depend on abnormal GluA2 mRNA editing but on selective downregulation of the GluA2 subunit by these neurons. Consistent with this, CP-AMPAR blockers promote robust RGC survival supporting a critical role for non-NMDA glutamate receptors in glaucomatous damage. This study identifies a novel mechanism by which glia-derived soluble TNFα modulates neuronal death in glaucoma.
The activation of self-destructive cellular programs helps sculpt the nervous system during development, but the molecular mechanisms used are not fully understood. Prior studies have investigated ...the role of the APP in the developmental degeneration of sensory neurons with contradictory results. In this work, we sought to elucidate the impact of APP deletion in the development of the sensory nervous system
and
Our
data show an increase in the number of sciatic nerve axons in adult male and female
mice, consistent with the hypothesis that APP plays a pro-degenerative role in the development of peripheral axons.
, we show that genetic deletion of APP delays axonal degeneration triggered by nerve growth factor deprivation, indicating that APP does play a pro-degenerative role. Interestingly, APP depletion does not affect caspase-3 levels but significantly attenuates the rise of axoplasmic Ca
that occurs during degeneration. We examined intracellular Ca
mechanisms that could be involved and found that
DRG neurons had increased Ca
levels within the endoplasmic reticulum and enhanced store-operated Ca
entry. We also observed that DRG axons lacking APP have more mitochondria than their WT counterparts, but these display a lower mitochondrial membrane potential. Finally, we present evidence that APP deficiency causes an increase in mitochondrial Ca
buffering capacity. Our results support the hypothesis that APP plays a pro-degenerative role in the developmental degeneration of DRG sensory neurons, and unveil the importance of APP in the regulation of calcium signaling in sensory neurons.
The nervous system goes through a phase of pruning and programmed neuronal cell death during development to reach maturity. In such context, the role played by the APP in the peripheral nervous system has been controversial, ranging from pro-survival to pro-degenerative. Here we present evidence
and
supporting the pro-degenerative role of APP, demonstrating the ability of APP to alter intracellular Ca
homeostasis and mitochondria, critical players of programmed cell death. This work provides a better understanding of the physiological function of APP and its implication in developmental neuronal death in the nervous system.
The activation of self-destructive cellular programs helps sculpt the nervous system during development, but the molecular mechanisms used are not fully understood. Prior studies have investigated ...the role of the APP in the developmental degeneration of sensory neurons with contradictory results. In this work, we sought to elucidate the impact of APP deletion in the development of the sensory nervous system in vivo and in vitro. Our in vivo data show an increase in the number of sciatic nerve axons in adult male and female APP-null mice, consistent with the hypothesis that APP plays a pro-degenerative role in the development of peripheral axons. In vitro, we show that genetic deletion of APP delays axonal degeneration triggered by nerve growth factor deprivation, indicating that APP does play a pro-degenerative role. Interestingly, APP depletion does not affect caspase-3 levels but significantly attenuates the rise of axoplasmic Ca2+ that occurs during degeneration. We examined intracellular Ca2+ mechanisms that could be involved and found that APP-null DRG neurons had increased Ca2+ levels within the endoplasmic reticulum and enhanced store-operated Ca2+ entry. We also observed that DRG axons lacking APP have more mitochondria than their WT counterparts, but these display a lower mitochondrial membrane potential. Finally, we present evidence that APP deficiency causes an increase in mitochondrial Ca2+ buffering capacity. Our results support the hypothesis that APP plays a pro-degenerative role in the developmental degeneration of DRG sensory neurons, and unveil the importance of APP in the regulation of calcium signaling in sensory neurons.
Extracellular S100B dramatically increases after brain injury. While low S100B levels are neuroprotective, micromolar S100B levels have shown in vitro to activate microglia and facilitate neuronal ...death. In astrocytes, S100B exposure activates nuclear factor kappa B (NF‐κB) and induces pro‐inflammatory mediators. On microglia and neurons S100B effects are essentially mediated by receptor for advanced glycation end products (RAGE)/NF‐κB, but it is not clear if these intracellular cascades are activated by different S100B levels in astrocytes and whether increased extracellular S100B is sufficient to induce reactive gliosis. A better understanding of these pathways is essential for developing successful strategies to preserve the beneficial S100B effects after brain injury. Here, we show that microglia‐depleted cultured astrocytes exposed to S100B mimicked several features of reactive gliosis by activating RAGE/Rac‐1‐Cdc42, RAGE/Erk‐Akt or RAGE/NF‐κB‐dependent pathways. S100B effects include RAGE/Rac1‐Cdc42‐dependent astroglial hypertrophy and facilitation of migration as well as increased mitosis. S100B exposure improved the astrocytic survival to oxidative stress, an effect that requires Erk/Akt. S100B also activates NF‐κB in a dose‐dependent manner; increases RAGE proximal promoter transcriptional activity and augmented endogenous RAGE expression. S100B‐exposed astrocytes showed a pro‐inflammatory phenotype with expression of Toll‐like receptor 2 (TLR 2), inducible nitric oxide synthase (iNOS) and interleukin 1‐beta (IL‐1β), and facilitated neuronal death induced by oxygen‐glucose deprivation. In vivo, intracerebral infusion of S100B was enough to induce an astroglial reactive phenotype. Together, these findings demonstrate that extracellular S100B in the micromolar level activates different RAGE‐dependent pathways that turn astrocytes into a pro‐inflammatory and neurodegenerative phenotype.
We propose that S100B turns astrocytes into a reactive phenotype in a RAGE‐dependent manner but engaging different intracellular pathways. While both nanomolar and micromolar S100B turn astrocytes into a reactive phenotype, micromolar S100B induces a conversion into a pro‐inflammatory‐neurodegenerative profile that facilitates neuronal death of OGD‐exposed neurons. We think that S100B/RAGE interaction is essential to expand reactive gliosis in the injured brain being a tempting target for limiting reactive gliosis to prevent the glial conversion into the neurodegenerative profile.
We propose that S100B turns astrocytes into a reactive phenotype in a RAGE‐dependent manner but engaging different intracellular pathways. While both nanomolar and micromolar S100B turn astrocytes into a reactive phenotype, micromolar S100B induces a conversion into a pro‐inflammatory‐neurodegenerative profile that facilitates neuronal death of OGD‐exposed neurons. We think that S100B/RAGE interaction is essential to expand reactive gliosis in the injured brain being a tempting target for limiting reactive gliosis to prevent the glial conversion into the neurodegenerative profile.
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