Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting ...NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of TRPM4 in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/TRPM4 complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate-responsive element-binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of stroke and retinal degeneration. Recombinant or small-molecule NMDAR/TRPM4 interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.
The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a ...regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium-driven adaptogenomics, leading to increased expression of inhibin β-A (inhba). Inhibin β-A (its homodimer is known as activin A) in turn reduces neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, thereby shielding neurons against mitochondrial dysfunction, a major cause of excitotoxicity. Thus, BDNF induces acquired neuroprotection by enhancing synaptic activity and lowering extrasynaptic NMDA receptor death signaling through a nuclear calcium-inhibin β-A pathway. This process, which confers protection against ischemic brain damage in a mouse stroke model, may be compromised in Huntington’s disease, Alzheimer’s disease, or aging-related neurodegenerative conditions that are associated with reduced BDNF levels and/or enhanced extrasynaptic NMDA receptor signaling.
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•BDNF-induced neuroprotection requires synaptic NMDA receptors and nuclear calcium•BDNF-nuclear calcium signaling induces transcription of inhba/activin A•Activin A reduces toxic extrasynaptic NMDA receptor signaling, shielding mitochondria•Activin A protects against excitotoxic cell death in cultured neurons and in vivo
Lau et al. show that BDNF-induced neuroprotection is mediated by synaptic NMDA-receptor-dependent nuclear calcium signals activating transcription of inhibin β-A (activin A). Activin A in turn reduces toxic extrasynaptic NMDA-receptor-mediated calcium influx, shields neurons from mitochondrial dysfunction, and protects against stroke-induced brain damage.
The role of neuronal dendrites is to receive and process synaptic inputs. The geometry of the dendritic arbor can undergo neuronal activity-dependent changes that may impact the cognitive abilities ...of the organism. Here we show that vascular endothelial growth factor D (VEGFD), commonly known as an angiogenic mitogen, controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus. VEGFD expression is dependent upon basal neuronal activity and requires nuclear calcium-calmodulin-dependent protein kinase IV (CaMKIV) signaling. Suppression of VEGFD expression in the mouse hippocampus by RNA interference causes memory impairments. Thus, nuclear calcium-VEGFD signaling mediates the effect of neuronal activity on the maintenance of dendritic arbors in the adult hippocampus and is required for cognitive functioning. These results suggest that caution be employed in the clinical use of blockers of VEGFD signaling for antiangiogenic cancer therapy.
► VEGFD expression is controlled by activity and nuclear calcium-CaMKIV signaling ► VEGFD regulates total dendrite length and complexity and is required for memory ► Results calls for caution in the use of VEGFD blockers in cancer therapy
Synaptic activity initiates many adaptive responses in neurons. Here we report a novel form of structural plasticity in dissociated hippocampal cultures and slice preparations. Using a recently ...developed algorithm for three-dimensional image reconstruction and quantitative measurements of cell organelles, we found that many nuclei from hippocampal neurons are highly infolded and form unequally sized nuclear compartments. Nuclear infoldings are dynamic structures, which can radically transform the geometry of the nucleus in response to neuronal activity. Action potential bursting causing synaptic NMDA receptor activation dramatically increases the number of infolded nuclei via a process that requires the ERK-MAP kinase pathway and new protein synthesis. In contrast, death-signaling pathways triggered by extrasynaptic NMDA receptors cause a rapid loss of nuclear infoldings. Compared with near-spherical nuclei, infolded nuclei have a larger surface and increased nuclear pore complex immunoreactivity. Nuclear calcium signals evoked by cytosolic calcium transients are larger in small nuclear compartments than in the large compartments of the same nucleus; moreover, small compartments are more efficient in temporally resolving calcium signals induced by trains of action potentials in the theta frequency range (5 Hz). Synaptic activity-induced phosphorylation of histone H3 on serine 10 was more robust in neurons with infolded nuclei compared with neurons with near-spherical nuclei, suggesting a functional link between nuclear geometry and transcriptional regulation. The translation of synaptic activity-induced signaling events into changes in nuclear geometry facilitates the relay of calcium signals to the nucleus, may lead to the formation of nuclear signaling microdomains, and could enhance signal-regulated transcription.
Abstract
The influence of the Intertropical Convergence Zone (ITCZ) in the emerging South Atlantic region during the late Aptian (Early Cretaceous) is reflected in the spatio-temporal distribution of ...plant communities recorded in eight Brazilian sedimentary basins. The distribution of the bioclimatic groups of hygrophytes, hydrophytes, tropical lowland flora, upland flora, and xerophytes was quantified using pollen and spores. A predominance of xerophytes from the tropical xerophytic shrubland biome characterized the pre-evaporitic, evaporitic, and post-evaporitic paleoclimatic phases, in particular the evaporitic phase. The region experienced humidity events in the pre-evaporitic and post- evaporitic phases, especially near the paleoequator, where the tropical rainforest biome with two phytophysiognomies (lowland and montane rainforests) prevailed. Increasing humidity had a positive effect on plant diversity.
A sample of 682 suture lines belonging to 204 Cretaceous planispiral ammonoid genera shows a positive, significant relationship between suture complexity (measured as fractal dimension Df) and ...generic longevity. However, during the Cretaceous there was no increase in the mean fractal dimension. This paradox is due to the evolutionary dynamic during this time span comprising mainly the appearance, disappearance (or anagenetic transformation) of those genera with simpler sutures and, consequently, the maximal values of fractal dimension were more stable in time. These results contrast with (i) the hypothesis that simple morphologies are linked to low ecological specialization and (ii) the idea that the role of natural selection can be unambiguously deduced from stratigraphic ranges.
The late Aptian (Early Cretaceous) is a crucial time interval for understanding the paleoceanographic changes in the Southern Hemisphere. Oceanographic changes in the emerging South Atlantic Ocean ...during this interval are reflected in the stratigraphic distribution of dinoflagellate communities recorded in the Muribeca and Riachuelo formations of the Sergipe Basin in northeastern Brazil. The Subtilisphaera community, in the lower and middle parts of the section, appears to be related to the Subtilisphaera Ecozone and suggests the onset of Tethyan influence in the central South Atlantic, in a restricted to inner‐neritic environment. The succeeding Spiniferites community, in the middle part of the section, represents the first significant transgression, probably of eustatic origin. The Cyclonephelium‐Exochosphaeridium community, in the upper part of the section, appears to be related to an oceanic event characterized by intermittent dysoxic‐anoxic conditions. The uppermost part of the section is dominated by the Spiniferites community, related to a progressive regional transgression and culminating in an open‐marine, fully Tethyan environment in the central part of the widening South Atlantic.
Key Points
Upper Aptian samples from the South Atlantic Ocean are examined
Three dinocyst communities identified in late Aptian
The oceanographic fluctuations is matched by the changes in dinocyst communities
Abstract
Glutamate toxicity is a pathomechanism that contributes to neuronal cell death in a wide range of acute and chronic neurodegenerative and neuroinflammatory diseases. Activation of the
N
...-methyl-D-aspartate (NMDA)-type glutamate receptor and breakdown of the mitochondrial membrane potential are key events during glutamate toxicity. Due to its manifold functions in nervous system physiology, however, the NMDA receptor is not well suited as a drug target. To identify novel compounds that act downstream of toxic NMDA receptor signaling and can protect mitochondria from glutamate toxicity, we developed a cell viability screening assay in primary mouse cortical neurons. In a proof-of-principle screen we tested 146 natural products and 424 FDA-approved drugs for their ability to protect neurons against NMDA-induced cell death. We confirmed several known neuroprotective drugs that include Dutasteride, Enalapril, Finasteride, Haloperidol, and Oxybutynin, and we identified neuroprotective properties of Elvitegravir. Using live imaging of tetramethylrhodamine ethyl ester-labelled primary cortical neurons, we found that Elvitegravir, Dutasteride, and Oxybutynin attenuated the NMDA-induced breakdown of the mitochondrial membrane potential. Patch clamp electrophysiological recordings in NMDA receptor-expressing HEK293 cell lines and primary mouse hippocampal neurons revealed that Elvitegravir does not act at the NMDA receptor and does not affect the function of glutamatergic synapses. In summary, we have developed a cost-effective and easy-to-implement screening assay in primary neurons and identified Elvitegravir as a neuro- and mitoprotective drug that acts downstream of the NMDA receptor.
MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the ...selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation.
This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’.
► Use-dependent recovery of NMDAR currents after MK-801 blockade is boosted by Mg2+. ► Use-dependent recovery is also accelerated by memantine. ► NMDA + Mg2+ can trigger 45% MK-801 dissociation in only 10 min ► NMDA + Mg2+ can promote death in neurons with NMDARs 100% pre-blocked by MK-801. ► Care should be taken not to overestimate the stability of MK-801 blockade of NMDARs.
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