Effects of Duration of Hypoxia, Temperature and ACSF Potassium Concentration on Probability of Recovery of CA1 Synaptic Function in the in vitro Rat Hippocampal Slice

2015 ◽  
pp. 143-146 ◽  
Author(s):  
K. H. Reid ◽  
A. Schurr ◽  
C. A. West
Keyword(s):  
Hippocampal Slice ◽  
Potassium Concentration ◽  
Synaptic Function

scholarly journals Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Anna R Moore ◽  
Sarah E Richards ◽  
Katelyn Kenny ◽  
Leandro Royer ◽  
Urann Chan ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Ocular Dominance ◽  
Sensory Experience ◽  
Cellular Level ◽  
Synaptic Function ◽  
Intrinsic Excitability ◽  
Spontaneous Firing ◽  
Circuit Function

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

scholarly journals Isoflurane Neurotoxicity Is Mediated by p75NTR-RhoA Activation and Actin Depolymerization

2011 ◽  
Vol 114 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Brian P. Lemkuil ◽  
Brian P. Head ◽  
Matthew L. Pearn ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Actin Depolymerization ◽  
Rhoa Activation ◽  
Hippocampal Slice Cultures ◽  
Developing Neurons

Background The mechanisms by which isoflurane injured the developing brain are not clear. Recent work has demonstrated that it is mediated in part by activation of p75 neurotrophin receptor. This receptor activates RhoA, a small guanosine triphosphatase that can depolymerize actin. It is therefore conceivable that inhibition of RhoA or prevention of cytoskeletal depolymerization might attenuate isoflurane neurotoxicity. This study was conducted to test these hypotheses using primary cultured neurons and hippocampal slice cultures from neonatal mouse pups. Methods Primary neuron cultures (days in vitro, 4-7) and hippocampal slice cultures from postnatal day 4-7 mice were exposed to 1.4% isoflurane (4 h). Neurons were pretreated with TAT-Pep5, an intracellular inhibitor of p75 neurotrophin receptor, the cytoskeletal stabilizer jasplakinolide, or their corresponding vehicles. Hippocampal slice cultures were pretreated with TAT-Pep5 before isoflurane exposure. RhoA activation was evaluated by immunoblot. Cytoskeletal depolymerization and apoptosis were evaluated with immunofluorescence microscopy using drebrin and cleaved caspase-3 staining, respectively. Results RhoA activation was increased after 30 and 120 min of isoflurane exposure in neurons; TAT-Pep5 (10 μm) decreased isoflurane-mediated RhoA activation at both time intervals. Isoflurane decreased drebrin immunofluorescence and enhanced cleaved caspase-3 in neurons, effects that were attenuated by pretreatment with either jasplakinolide (1 μm) or TAT-Pep5. TAT-Pep5 attenuated the isoflurane-mediated decrease in phalloidin immunofluorescence. TAT-Pep5 significantly attenuated isoflurane-mediated loss of drebrin immunofluorescence in hippocampal slices. Conclusions Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis. Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity in developing neurons.

scholarly journals CSPα reduces aggregates and rescues striatal dopamine release in αsynuclein transgenic mice

2020 ◽  
Author(s):  
L Caló ◽  
E Hidari ◽  
M Wegrzynowicz ◽  
JW Dalley ◽  
BL Schneider ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Early Stage ◽  
Synaptic Function ◽  
Snare Complex ◽  
Early Event ◽  
Vesicle Recycling ◽  
Cysteine String Protein ◽  
And Function

AbstractαSynuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and αsynuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like αsynuclein, chaperones the SNARE complex assembly and neurotransmitter release. αSynuclein can rescue neurodegeneration in CSPαKO mice. However, whether αsynuclein aggregation alters CSPα expression and function is unknown. Here we show that αsynuclein aggregation at the synapse induces a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with αsynuclein aggregates and in vivo reduces synaptic αsynuclein aggregates restoring normal dopamine release in 1-120hαsyn mice. These novel findings reveal a mechanism by which αsynuclein aggregation alters CSPα at the synapse, and show that CSPα rescues αsynuclein aggregation-related phenotype in 1-120hαsyn mice similar to the effect of αsynuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage PD.

scholarly journals Does Impairment of Adult Neurogenesis Contribute to Pathophysiology of Alzheimer's Disease? A Still Open Question

2021 ◽  
Vol 13 ◽  
Author(s):  
Domenica Donatella Li Puma ◽  
Roberto Piacentini ◽  
Claudio Grassi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Adult Neurogenesis ◽  
Memory Formation ◽  
Hippocampal Neurogenesis ◽  
Synaptic Function ◽  
Adult Hippocampal Neurogenesis ◽  
Amyloid Β Protein

Adult hippocampal neurogenesis is a physiological mechanism contributing to hippocampal memory formation. Several studies associated altered hippocampal neurogenesis with aging and Alzheimer's disease (AD). However, whether amyloid-β protein (Aβ)/tau accumulation impairs adult hippocampal neurogenesis and, consequently, the hippocampal circuitry, involved in memory formation, or altered neurogenesis is an epiphenomenon of AD neuropathology contributing negligibly to the AD phenotype, is, especially in humans, still debated. The detrimental effects of Aβ/tau on synaptic function and neuronal viability have been clearly addressed both in in vitro and in vivo experimental models. Until some years ago, studies carried out on in vitro models investigating the action of Aβ/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions (e.g., different cellular/animal models, different Aβ and/or tau isoforms, concentrations, and/or aggregation profiles). To date, studies investigating in situ adult hippocampal neurogenesis indicate severe impairment in most of transgenic AD mice; this impairment precedes by several months cognitive dysfunction. Using experimental tools, which only became available in the last few years, research in humans indicated that hippocampal neurogenesis is altered in cognitive declined individuals affected by either mild cognitive impairment or AD as well as in normal cognitive elderly with a significant inverse relationship between the number of newly formed neurons and cognitive impairment. However, despite that such information is available, the question whether impaired neurogenesis contributes to AD pathogenesis or is a mere consequence of Aβ/pTau accumulation is not definitively answered. Herein, we attempted to shed light on this complex and very intriguing topic by reviewing relevant literature on impairment of adult neurogenesis in mouse models of AD and in AD patients analyzing the temporal relationship between the occurrence of altered neurogenesis and the appearance of AD hallmarks and cognitive dysfunctions.

scholarly journals Identification of Neuronal Pentraxins as Synaptic Binding Partners of C1q and the Involvement of NP1 in Synaptic Pruning in Adult Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Réka Á. Kovács ◽  
Henrietta Vadászi ◽  
Éva Bulyáki ◽  
György Török ◽  
Vilmos Tóth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Potential Interaction ◽  
Synaptic Function ◽  
Classical Pathway ◽  
Microglial Phagocytosis ◽  
Classical Complement Pathway ◽  
Adult Mice ◽  
Synaptic Pruning

Elements of the immune system particularly that of innate immunity, play important roles beyond their traditional tasks in host defense, including manifold roles in the nervous system. Complement-mediated synaptic pruning is essential in the developing and healthy functioning brain and becomes aberrant in neurodegenerative disorders. C1q, component of the classical complement pathway, plays a central role in tagging synapses for elimination; however, the underlying molecular mechanisms and interaction partners are mostly unknown. Neuronal pentraxins (NPs) are involved in synapse formation and plasticity, moreover, NP1 contributes to cell death and neurodegeneration under adverse conditions. Here, we investigated the potential interaction between C1q and NPs, and its role in microglial phagocytosis of synapses in adult mice. We verified in vitro that NPs interact with C1q, as well as activate the complement system. Flow cytometry, immunostaining and co-immunoprecipitation showed that synapse-bound C1q colocalizes and interacts with NPs. High-resolution confocal microscopy revealed that microglia-surrounded C1q-tagged synapses are NP1 positive. We have also observed the synaptic occurrence of C4 suggesting that activation of the classical pathway cannot be ruled out in synaptic plasticity in healthy adult animals. In summary, our results indicate that NPs play a regulatory role in the synaptic function of C1q. Whether this role can be intensified upon pathological conditions, such as in Alzheimer’s disease, is to be disclosed.

Long-term Adaptations of Sabella Giant Axons to Hyposmotic Stress

1978 ◽  
Vol 75 (1) ◽  
pp. 253-263
Author(s):  
J. E. TREHERNE ◽  
Y. PICHON
Keyword(s):  
Sea Water ◽  
Potassium Concentration ◽  
Resting Potential ◽  
Sodium Permeability ◽  
Bathing Medium ◽  
Appreciable Change ◽  
Axon Membrane ◽  
Giant Axons

Reprint requests should be addressed to Dr Treherne. Sabella is a euryhaline osmoconformer which is killed by direct transfer to 50% sea water, but can adapt to this salinity with progressive dilution of the sea water. The giant axons were adapted to progressive dilution of the bathing medium (both in vivo and in vitro) and were able to function at hyposmotic dilutions (down to 50%) sufficient to induce conduction block in unadapted axons. Hyposmotic adaptation of the giant axon involves a decrease in intracellular potassium concentration which tends to maintain a relatively constant resting potential during adaptation despite the reduction in external potassium concentration. There is no appreciable change in the intracellular sodium concentration, but the relative sodium permeability of the active membrane increases during hyposmotic adaptation. This increase partially compensates for the reduction in sodium gradient across the axon membrane, during dilution of the bathing media, by increasing the overshoot of the action potentials recorded in hyposmotically adapted axons.

Intake of Flavonoids from Astragalus Membranaceus Ameliorated Brain Impairment in Diabetic Mice Via Modulating Brain-Gut Axis

2021 ◽  
Author(s):  
Li Xuling ◽  
Junling Gu ◽  
Zhe Wang ◽  
Jing Lin ◽  
Tingting Zhao ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Brain Damage ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Synaptic Function ◽  
Astragalus Membranaceus ◽  
Immunological Methods ◽  
Diabetic Mice ◽  
High Fat

Abstract Background: Brain impairment is one of a major complication of diabetes. Dietary flavonoids have been recommended to prevent brain damage. Astragalus membranaceus is a herbal medicine commonly used to relieve the complications of diabetes. Flavonoids is one of the major ingredients of Astragalus membranaceus, but its function and mechanism on diabetic encepholopathy is still unknown.Methods: Type 2 diabetes mellitus (T2DM) model was induced by high fat diet and STZ in C57BL/6J mice, and BEnd.3 and HT22 cell lines were applied in the in vitro study. Quality of flavonoids was evaluated by LC-MS/MS. Differential expressed proteins in the hippocampus were evaluated by proteomics; influence of the flavonoids on composition of gut microbiota was analyzed by metagenomics. Mechanism of the flavonoids on diabetic encepholopathy was analyzed by Q-PCR, Western Blot, and multi-immunological methods et al. Results: We found that flavonoids from Astragalus membranaceus (TFA) significantly ameliorated brain damage by modulating gut-microbiota-brain axis: TFA oral administration decreased fasting blood glucose and food intake, repaired blood brain barrier, protected hippocampus synaptic function; improved hippocampus mitochondrial biosynthesis and energy metabolism; and enriched the intestinal microbiome in high fat diet/STZ-induced diabetic mice. In the in vitro study, we found TFA increased viability of HT22 cells and preserved gut barrier integrity in CaCO2 monocellular layer, and PGC1α/AMPK pathway participated in this process. Conclusion: Our findings demonstrated that flavonoids from Astragalus Membranaceus ameliorated brain impairment via gut-brain axis. Our present study provided an alternative solution on preventing and treating diabetic cognition impairment.

scholarly journals APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

2020 ◽  
Vol 21 (4) ◽  
pp. 1413 ◽  
Author(s):  
Takami Tomiyama ◽  
Hiroyuki Shimada
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Synaptic Function ◽  
Recessive Inheritance ◽  
Familial Alzheimer’S Disease ◽  
Aβ Oligomers ◽  
Unique Character ◽  
Familial Alzheimer's Disease

Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer’s disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer’s disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant’s phenotypes, and propose a mechanism of its recessive inheritance.

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