scholarly journals The Impact of Oxytocin on Neurite Outgrowth and Synaptic Proteins in Magel2-Deficient Mice

2020 ◽  
Author(s):  
Alexandra Reichova ◽  
Fabienne Schaller ◽  
Stanislava Bukatova ◽  
Zuzana Bacova ◽  
Françoise Muscatelli ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Primary Cultures ◽  
Synaptic Proteins ◽  
Neuronal Maturation ◽  
Glutamatergic Synapses ◽  
Associated Proteins ◽  
The Impact ◽  
Deficient Mice

AbstractOxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could therefore affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin, but not retinoic acid, reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect in development that should be considered for certain neuropsychiatric conditions in infancy.

scholarly journals The Impact of Oxytocin on Neurite Outgrowth and Synaptic Proteins in Magel2 ‐Deficient Mice

2021 ◽  
Author(s):  
Alexandra Reichova ◽  
Fabienne Schaller ◽  
Stanislava Bukatova ◽  
Zuzana Bacova ◽  
Françoise Muscatelli ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Synaptic Proteins ◽  
The Impact ◽  
Deficient Mice

Inhibition of neuronal maturation in primary hippocampal neurons from τ deficient mice

2001 ◽  
Vol 114 (6) ◽  
pp. 1179-1187 ◽  
Author(s):  
H.N. Dawson ◽  
A. Ferreira ◽  
M.V. Eyster ◽  
N. Ghoshal ◽  
L.I. Binder ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Axonal Growth ◽  
Neuronal Maturation ◽  
Significant Delay ◽  
Microtubule Associated Proteins ◽  
Conflicting Evidence ◽  
Associated Proteins ◽  
Classic Technique ◽  
Τ Protein ◽  
Deficient Mice

Conflicting evidence supports a role for τ as an essential neuronal cytoskeletal protein or as a redundant protein whose function can be fulfilled by other microtubule-associated proteins. To investigate the function of τ in axonogenesis, we created τ deficient mice by disrupting the TAU gene. The engineered mice do not express the τ protein, appear physically normal and are able to reproduce. In contrast to a previously reported τ knockout mouse, embryonic hippocampal cultures from τ deficient mice show a significant delay in maturation as measured by axonal and neuritic extensions. The classic technique of selectively enhancing axonal growth by growth on laminin substrates failed to restore normal neuronal maturation of τ knockout neurons. By mating human TAU-gene transgenic and τ knockout mice, we reconstituted τ-deficient neurons with human τ proteins and restored a normal pattern of axonal growth and neuronal maturation. The ability of human τ proteins to rescue τ-deficient mouse neurons confirms that τ expression affects the rate of neurite extension.

scholarly journals Colocalization of synaptophysin with transferrin receptors: implications for synaptic vesicle biogenesis.

1991 ◽  
Vol 115 (1) ◽  
pp. 151-164 ◽  
Author(s):  
P L Cameron ◽  
T C Südhof ◽  
R Jahn ◽  
P De Camilli
Keyword(s):  
Synaptic Vesicle ◽  
Cell Lines ◽  
Endocrine Cell ◽  
Cho Cells ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Primary Cultures ◽  
Endocytic Pathway ◽  
Transferrin Receptors ◽  
Vesicle Biogenesis

We have reported previously that the synaptic vesicle (SV) protein synaptophysin, when expressed in fibroblastic CHO cells, accumulates in a population of recycling microvesicles. Based on preliminary immunofluorescence observations, we had suggested that synaptophysin is targeted to the preexisting population of microvesicles that recycle transferrin (Johnston, P. A., P. L. Cameron, H. Stukenbrok, R. Jahn, P. De Camilli, and T. C. Südhof. 1989. EMBO (Eur. Mol. Biol. Organ.) J. 8:2863-2872). In contrast to our results, another group reported that expression of synaptophysin in cells which normally do not express SV proteins results in the generation of a novel population of microvesicles (Leube, R. E., B. Wiedenmann, and W. W. Franke. 1989. Cell. 59:433-446). We report here a series of morphological and biochemical studies conclusively demonstrating that synaptophysin and transferrin receptors are indeed colocalized on the same vesicles in transfected CHO cells. These observations prompted us to investigate whether an overlap between the distribution of the two proteins also occurs in endocrine cell lines that endogenously express synaptophysin and other SV proteins. We have found that endocrine cell lines contain two pools of membranes positive for synaptophysin and other SV proteins. One of the two pools also contains transferrin receptors and migrates faster during velocity centrifugation. The other pool is devoid of transferrin receptors and corresponds to vesicles with the same sedimentation characteristics as SVs. These findings suggest that in transfected CHO cells and in endocrine cell lines, synaptophysin follows the same endocytic pathway as transferrin receptors but that in endocrine cells, at some point along this pathway, synaptophysin is sorted away from the recycling receptors into a specialized vesicle population. Finally, using immunofluorescent analyses, we found an overlap between the distribution of synaptophysin and transferrin receptors in the dendrites of hippocampal neurons in primary cultures before synapse formation. Axons were enriched in synaptophysin immunoreactivity but did not contain detectable levels of transferrin receptor immunoreactivity. These results suggest that SVs may have evolved from, as well as coexist with, a constitutively recycling vesicular organelle found in all cells.

scholarly journals Medroxyprogesterone Acetate Antagonizes Estrogen Up-Regulation of Brain Mitochondrial Function

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 556-567 ◽  
Author(s):  
Ronald W. Irwin ◽  
Jia Yao ◽  
Syeda S. Ahmed ◽  
Ryan T. Hamilton ◽  
Enrique Cadenas ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Mitochondrial Function ◽  
Medroxyprogesterone Acetate ◽  
Hippocampal Neurons ◽  
Manganese Superoxide Dismutase ◽  
Primary Cultures ◽  
Mitochondrial Protein ◽  
Female Rats ◽  
Manganese Superoxide ◽  
The Impact

Abstract The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.

scholarly journals Light induced synaptic vesicle autophagy

2018 ◽  
Author(s):  
Sheila Hoffmann ◽  
Marta Orlando ◽  
Ewa Andrzejak ◽  
Thorsten Trimbuch ◽  
Christian Rosenmund ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Real Time ◽  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Oxygen Species ◽  
Local Damage ◽  
Glutamatergic Synapses ◽  
Presynaptic Boutons ◽  
Presynaptic Proteins

AbstractThe regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated and whether SVs are cleared en-mass together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real time to support synaptic health. To address these questions, we have developed an imaging based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light activated reactive oxygen species (ROS) generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons, presynaptic autophagy can be induced in as little as 5-10 minutes and eliminates primarily the damaged protein rather than the SV en-mass. Importantly, we also find that autophagy is essential for synaptic function, as light-induced damage to e.g. Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.Significance StatementThe real-time surveillance and clearance of synaptic proteins is thought to be vital to the health, functionality and integrity of vertebrate synapses and is compromised in neurodegenerative disorders, yet the fundamental mechanisms regulating these systems remain enigmatic. Our analysis reveals that presynaptic autophagy is a critical part of a real-time clearance system at glutamatergic synapses capable of responding to local damage of synaptic vesicle proteins within minutes and to be critical for the ongoing functionality of these synapses. These data indicate that synapse autophagy is not only locally regulated but also crucial for the health and functionality of vertebrate presynaptic boutons.

scholarly journals Defects in Axonal Elongation and Neuronal Migration in Mice with Disrupted tau and map1b Genes

2000 ◽  
Vol 150 (5) ◽  
pp. 989-1000 ◽  
Author(s):  
Yosuke Takei ◽  
Junlin Teng ◽  
Akihiro Harada ◽  
Nobutaka Hirokawa
Keyword(s):  
Knockout Mice ◽  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Double Knockout ◽  
Microtubule Organization ◽  
Axonal Elongation ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

Tau and MAP1B are the main members of neuronal microtubule-associated proteins (MAPs), the functions of which have remained obscure because of a putative functional redundancy (Harada, A., K. Oguchi, S. Okabe, J. Kuno, S. Terada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 1994. Nature. 369:488–491; Takei, Y., S. Kondo, A. Harada, S. Inomata, T. Noda, and N. Hirokawa. 1997. J. Cell Biol. 137:1615–1626). To unmask the role of these proteins, we generated double-knockout mice with disrupted tau and map1b genes and compared their phenotypes with those of single-knockout mice. In the analysis of mice with a genetic background of predominantly C57Bl/6J, a hypoplastic commissural axon tract and disorganized neuronal layering were observed in the brains of the tau+/+map1b−/− mice. These phenotypes are markedly more severe in tau−/−map1b−/− double mutants, indicating that tau and MAP1B act in a synergistic fashion. Primary cultures of hippocampal neurons from tau−/−map1b−/− mice showed inhibited axonal elongation. In these cells, a generation of new axons via bundling of microtubules at the neck of the growth cones appeared to be disturbed. Cultured cerebellar neurons from tau−/−map1b−/− mice showed delayed neuronal migration concomitant with suppressed neurite elongation. These findings indicate the cooperative functions of tau and MAP1B in vivo in axonal elongation and neuronal migration as regulators of microtubule organization.

scholarly journals Synapse Formation by Hippocampal Neurons from Agrin-Deficient Mice

1999 ◽  
Vol 205 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Anna S. Serpinskaya ◽  
Guoping Feng ◽  
Joshua R. Sanes ◽  
Ann Marie Craig
Keyword(s):  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Deficient Mice

Cellular prion protein mediates laminin-dependent neurite outgrowth in primary cultures of rat and mouse hippocampal neurons

2000 ◽  
Vol 21 ◽  
pp. 52
Author(s):  
Orestes V. Forlenza ◽  
Silvio M. Zanata ◽  
Edgard Graner ◽  
Adriana F. Mercadante ◽  
Vilma R. Martins ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Prion Protein ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Cellular Prion Protein

scholarly journals Distance-dependent regulation of NMDAR nanoscale organization along hippocampal neuron dendrites

2020 ◽  
Vol 117 (39) ◽  
pp. 24526-24533
Author(s):  
Joana S. Ferreira ◽  
Julien P. Dupuis ◽  
Blanka Kellermayer ◽  
Nathan Bénac ◽  
Constance Manso ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Dendritic Tree ◽  
Synaptic Proteins ◽  
Glutamatergic Synapses ◽  
Action Potential Firing ◽  
Hippocampal Pyramidal Neurons ◽  
Calcium Calmodulin Dependent ◽  
Potential Firing ◽  
Nanoscale Topography

Hippocampal pyramidal neurons are characterized by a unique arborization subdivided in segregated dendritic domains receiving distinct excitatory synaptic inputs with specific properties and plasticity rules that shape their respective contributions to synaptic integration and action potential firing. Although the basal regulation and plastic range of proximal and distal synapses are known to be different, the composition and nanoscale organization of key synaptic proteins at these inputs remains largely elusive. Here we used superresolution imaging and single nanoparticle tracking in rat hippocampal neurons to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDA receptors (NMDARs)—which play key roles in the use-dependent adaptation of glutamatergic synapses—along the dendritic arbor. We report significant changes in the nanoscale organization of GluN2B-NMDARs between proximal and distal dendritic segments, whereas the topography of GluN2A-NMDARs remains similar along the dendritic tree. Remarkably, the nanoscale organization of GluN2B-NMDARs at proximal segments depends on their interaction with calcium/calmodulin-dependent protein kinase II (CaMKII), which is not the case at distal segments. Collectively, our data reveal that the nanoscale organization of NMDARs changes along dendritic segments in a subtype-specific manner and is shaped by the interplay with CaMKII at proximal dendritic segments, shedding light on our understanding of the functional diversity of hippocampal glutamatergic synapses.

scholarly journals EphA activation overrides the presynaptic actions of BDNF

2011 ◽  
Vol 105 (5) ◽  
pp. 2364-2374 ◽  
Author(s):  
Caixia Bi ◽  
Xin Yue ◽  
Renping Zhou ◽  
Mark R. Plummer
Keyword(s):  
Neurite Outgrowth ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Brain Derived Neurotrophic Factor ◽  
Synaptic Activity ◽  
Neural Connectivity ◽  
Current Frequency ◽  
Adult Pattern ◽  
Electrophysiological Effects

The adult pattern of neural connectivity is shaped by repulsive and attractive factors, many of which are modulated by activity. Although much is known about the actions of these factors when studied in isolation, little is known about how they interact. To address this question, we examined the effects of sequential or coapplication of brain-derived neurotrophic factor (BDNF) and Fc-conjugated ephrin-A5 or EphA5 in cultured embryonic hippocampal neurons. BDNF promotes neurite outgrowth and synapse formation, and when applied acutely, it elicits an increase in ongoing synaptic activity. Members of the ephrin family of ligands and receptors can be repulsive and prevent formation of synaptic contacts. Acute exposure to either ephrin-A5-Fc or EphA5-Fc transiently enhanced synaptic activity when applied alone, but when applied prior to BDNF, they dramatically reduced the electrophysiological effects of the neurotrophin. Conversely, BDNF had no effect on subsequently applied ephrin-A5-Fc or EphA5-Fc. Consistent with this, ephrin-A5-Fc also prevented BDNF-induced activation of p42/44 MAPK. The effect of ephrin-A5-Fc appears to be presynaptic, as it prevented the BDNF-induced increase in spontaneous miniature postsynaptic current frequency, whereas EphA5-Fc did not. These results suggest that these factors can be categorized differently, with the contact-mediated activation of EphA receptors by ephrin-A5 overriding the diffusion-mediated effect of BDNF.

Sign in / Sign up

Export Citation Format

Share Document