scholarly journals Identification of the SNARE complex mediating the exocytosis of NMDA receptors

2016 ◽  
Vol 113 (43) ◽  
pp. 12280-12285 ◽  
Author(s):  
Yi Gu ◽  
Richard L. Huganir
Keyword(s):  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
Total Internal Reflection ◽  
De Novo ◽  
Receptor Trafficking ◽  
Snare Complex ◽  
Synaptic Membranes ◽  
Rab Proteins ◽  
The Central Nervous System ◽  
The Brain

In the central nervous system, NMDA receptors mediate excitatory neurotransmissions and play important roles in synaptic plasticity. The regulation of NMDA receptor trafficking is critical for neural functions in the brain. Here, we directly visualized individual exocytic events of NMDA receptors in rat hippocampal neurons by total internal reflection fluorescence microscopy (TIRFM). We found that the constitutive exocytosis of NMDA receptors included both de novo exocytic and recycling events, which were regulated by different Rab proteins. We also identified the SNAP25–VAMP1–syntaxin4 complex mediating the constitutive exocytosis of NMDA receptors. Transient knockdown of each component of the SNARE complex interfered with surface delivery of NMDA receptors to both extrasynaptic and synaptic membranes. Our study uncovers the postsynaptic function of the SNAP25–VAMP1–syntaxin4 complex in mediating the constitutive exocytosis of NMDA receptors, suggesting that this SNARE complex is involved in excitatory synaptic transmission.

scholarly journals A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Dany Khamsing ◽  
Solène Lebrun ◽  
Isabelle Fanget ◽  
Nathanaël Larochette ◽  
Christophe Tourain ◽  
...  
Keyword(s):  
Amino Acids ◽  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Long Term Potentiation ◽  
Activation Mechanism ◽  
Functional Link ◽  
Term Potentiation ◽  
Endocytic Compartments ◽  
Mtorc1 Activation

AbstractMemory and long term potentiation require de novo protein synthesis. A key regulator of this process is mTORC1, a complex comprising the mTOR kinase. Growth factors activate mTORC1 via a pathway involving PI3-kinase, Akt, the TSC complex and the GTPase Rheb. In non-neuronal cells, translocation of mTORC1 to late endocytic compartments (LEs), where Rheb is enriched, is triggered by amino acids. However, the regulation of mTORC1 in neurons remains unclear. In mouse hippocampal neurons, we observed that BDNF and treatments activating NMDA receptors trigger a robust increase in mTORC1 activity. NMDA receptors activation induced a significant recruitment of mTOR onto lysosomes even in the absence of external amino acids, whereas mTORC1 was evenly distributed in neurons under resting conditions. NMDA receptor-induced mTOR translocation to LEs was partly dependent on the BDNF receptor TrkB, suggesting that BDNF contributes to the effect of NMDA receptors on mTORC1 translocation. In addition, the combination of Rheb overexpression and artificial mTORC1 targeting to LEs by means of a modified component of mTORC1 fused with a LE-targeting motif strongly activated mTOR. To gain spatial and temporal control over mTOR localization, we designed an optogenetic module based on light-sensitive dimerizers able to recruit mTOR on LEs. In cells expressing this optogenetic tool, mTOR was translocated to LEs upon photoactivation. In the absence of growth factor, this was not sufficient to activate mTORC1. In contrast, mTORC1 was potently activated by a combination of BDNF and photoactivation. The data demonstrate that two important triggers of synaptic plasticity, BDNF and NMDA receptors, synergistically power the two arms of the mTORC1 activation mechanism, i.e., mTORC1 translocation to LEs and Rheb activation. Moreover, they unmask a functional link between NMDA receptors and mTORC1 that could underlie the changes in the synaptic proteome associated with long-lasting changes in synaptic strength.

scholarly journals Fatty Acids in Energy Metabolism of the Central Nervous System

2014 ◽  
Vol 2014 ◽  
pp. 1-22 ◽  
Author(s):  
Alexander Panov ◽  
Zulfiya Orynbayeva ◽  
Valentin Vavilin ◽  
Vyacheslav Lyakhovich
Keyword(s):  
Fatty Acids ◽  
Energy Metabolism ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Metabolic Phenotype ◽  
Neuronal Excitation ◽  
Palmitoyl Carnitine ◽  
The Central Nervous System ◽  
Mitochondrial Oxidation ◽  
The Brain

In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain’s energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcileβ-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.

scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Critical Role ◽  
Er Stress Response ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b−/− mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in hippocampi of Atf6b−/− and Calr+/− mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

scholarly journals Kynurenine Pathway Metabolism is Involved in the Maintenance of the Intracellular NAD+ Concentration in Human Primary Astrocytes

2010 ◽  
Vol 3 ◽  
pp. IJTR.S4779 ◽  
Author(s):  
Ross Grant ◽  
Susan Nguyen ◽  
Gilles Guillemin
Keyword(s):  
Nicotinic Acid ◽  
De Novo ◽  
Culture Media ◽  
Kynurenine Pathway ◽  
The Body ◽  
Tryptophan Degradation ◽  
Major Cell Type ◽  
The Central Nervous System ◽  
The Relationship ◽  
The Brain

Efficient synthesis of NAD+ is critical to maintaining cell viability in all organs of the body. However, little is known of the pathway(s) by which cells of the central nervous system produce NAD+. The aim of this study was to investigate the relationship, between tryptophan degradation via the kynurenine pathway (KP) and de novo NAD+ synthesis in human astrocytes, a major cell type within the brain. In this study we observed that inhibition of single enzymes of the KP resulted in significant decreases in NAD+ levels in astroglial cells after a 24 hr period. We also observed that astrocytes cultured in media deficient in tryptophan, nicotinic acid and nicotinamide resulted in a 50% decrease in NAD+ levels after 24 hrs. This decrease in NAD+ was partially restored by supplementation of the culture media with either tryptophan or kynurenine, or nicotinic acid or with supply of the salvage pathway precursor nicotinamide.

scholarly journals Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Sylwia Owczarek ◽  
Marie Louise Bang ◽  
Vladimir Berezin
Keyword(s):  
Central Nervous System ◽  
Cell Adhesion Molecules ◽  
Synaptic Membranes ◽  
Dependent Manner ◽  
Related Protein ◽  
Synaptic Complex ◽  
The Central Nervous System ◽  
And Function ◽  
Activity Dependent ◽  
The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

Exposure to 835 MHz radiofrequency electromagnetic field induces autophagy in hippocampus but not in brain stem of mice

2017 ◽  
Vol 34 (1) ◽  
pp. 23-35 ◽  
Author(s):  
Ju Hwan Kim ◽  
Da-Hyeon Yu ◽  
Hyo-Jeong Kim ◽  
Yang Hoon Huh ◽  
Seong-Wan Cho ◽  
...  
Keyword(s):  
Brain Stem ◽  
Mobile Phones ◽  
Hippocampal Neurons ◽  
Brain Regions ◽  
Pcr Analysis ◽  
Limited Information ◽  
The Central Nervous System ◽  
Neuronal Functions ◽  
Adaptation Processes ◽  
The Brain

The exploding popularity of mobile phones and their close proximity to the brain when in use has raised public concern regarding possible adverse effects from exposure to radiofrequency electromagnetic fields (RF-EMF) on the central nervous system. Numerous studies have suggested that RF-EMF emitted by mobile phones can influence neuronal functions in the brain. Currently, there is still very limited information on what biological mechanisms influence neuronal cells of the brain. In the present study, we explored whether autophagy is triggered in the hippocampus or brain stem after RF-EMF exposure. C57BL/6 mice were exposed to 835 MHz RF-EMF with specific absorption rates (SAR) of 4.0 W/kg for 12 weeks; afterward, the hippocampus and brain stem of mice were dissected and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that several autophagic genes, which play key roles in autophagy regulation, were significantly upregulated only in the hippocampus and not in the brain stem. Expression levels of LC3B-II protein and p62, crucial autophagic regulatory proteins, were significantly changed only in the hippocampus. In parallel, transmission electron microscopy (TEM) revealed an increase in the number of autophagosomes and autolysosomes in the hippocampal neurons of RF-EMF-exposed mice. The present study revealed that autophagy was induced in the hippocampus, not in the brain stem, in 835 MHz RF-EMF with an SAR of 4.0 W/kg for 12 weeks. These results could suggest that among the various adaptation processes to the RF-EMF exposure environment, autophagic degradation is one possible mechanism in specific brain regions.

scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Er Stress Response ◽  
Intracellular Ca ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

scholarly journals A peroxisome deficiency–induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway

2020 ◽  
Vol 295 (16) ◽  
pp. 5321-5334 ◽  
Author(s):  
Yuichi Abe ◽  
Masanori Honsho ◽  
Ryoko Kawaguchi ◽  
Takashi Matsuzaki ◽  
Yayoi Ichiki ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Cell Communication ◽  
Brain Derived Neurotrophic Factor ◽  
Bdnf Expression ◽  
Multiple Organs ◽  
The Central Nervous System ◽  
And Function ◽  
The Brain

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Hippocampus is more vulnerable to neural damages induced by repeated sevoflurane exposure in the second trimester than other brain areas

2020 ◽  
Vol 52 (8) ◽  
pp. 864-874
Author(s):  
Bing Chen ◽  
Yanjun Liu ◽  
Yirong Cai ◽  
Dan Tang ◽  
Saihong Xu ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Brain Regions ◽  
Sensitive Period ◽  
Second Trimester ◽  
Brain Areas ◽  
Axon Development ◽  
The Central Nervous System ◽  
New Perspective ◽  
Anesthetic Exposure ◽  
The Brain

Abstract During the rapidly developing and sensitive period of the central nervous system (CNS), a harmful stimulus may have serious consequences. The effect of anesthetic exposure on the development of the offspring’s CNS during pregnancy is still unclear and has been widely concerned. In the present study, we compared the susceptibility of the hippocampus with those of other brain regions in offsprings when the mother mice were exposed to repeated sevoflurane. We found that other than affecting motor sensation, emotion, or social behavior of offspring mice, repeated sevoflurane exposure induced significant memory deficiency. Compared with other brain regions, the hippocampus, which is the key component of the brain serving for learning and memory, was more vulnerable to repeated sevoflurane exposure. We also found that repeated sevoflurane exposure to mother mice could inhibit the axon development of hippocampal neurons. We also predicted that N6-methyladenosine modification of mRNA might play an essential role in the vulnerability of the hippocampus to sevoflurane, while the underlying cellular mechanism needs to be explored in the future. Our study may provide a new perspective for studying the mechanism of hippocampus-specific injury induced by sevoflurane exposure.

scholarly journals The ATF6β-Calreticulin Axis Promotes Neuronal Survival Under Endoplasmic Reticulum Stress and Excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Er Stress Response ◽  
Intracellular Ca ◽  
The Central Nervous System ◽  
The Brain

Abstract While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its homologue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

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