scholarly journals DL-3-n-butylphthalide enhances synaptic plasticity in mouse model of brain impairments

STEMedicine ◽  
2022 ◽  
Vol 3 (1) ◽  
pp. e113
Author(s):  
Qian Ding ◽  
Qian Yu ◽  
Lei Tao ◽  
Yifei Guo ◽  
Juan Zhao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Glutamate Release ◽  
Field Potential ◽  
Nmda Receptor Subunits ◽  
Glutamate Level ◽  
Regulatory Effects ◽  
Glutaminase Activity

Synaptic impairment results in cognitive dysfunction of Alzheimer’s disease (AD). As a plant extract, it is found that DL-3-n-butylphthalide (L-NBP) rescues abnormal cognitive behaviors in AD animals. However, the regulatory effects of L-NBP on synaptic plasticity remains unclear. APP/PS1 mice at 12 months old received oral L-NBP treatment for 12 weeks. A water maze test assessed cognitive performances. In vitro patch-clamp recordings and in vivo field potential recordings were performed to evaluate synaptic plasticity. The protein expression of AMPA receptor subunits (GluR1 and GluR2) and NMDA receptor subunits (NR1, NR2A, and NR2B) was examined by Western blot. In addition, glutaminase activity and glutamate level in the hippocampus were measured by colorimetry to evaluate presynaptic glutamate release. L-NBP treatment could significantly improve learning and memory ability, upregulate NR2A and NR2B protein expressions, increase glutaminase activity and glutamate level in the hippocampus, and attenuate synaptic impairment transmission in the AD mice. L-NPB plays a beneficial role in AD mice by regulating NMDA receptor subunits’ expression and regulating presynaptic glutamate release.

scholarly journals NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

2007 ◽  
Vol 27 (11) ◽  
pp. 2846-2857 ◽  
Author(s):  
Y. Liu ◽  
T. P. Wong ◽  
M. Aarts ◽  
A. Rooyakkers ◽  
L. Liu ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Neuronal Death ◽  
Nmda Receptor Subunits ◽  
Excitotoxic Neuronal Death

scholarly journals ATP11B deficiency leads to impairment of hippocampal synaptic plasticity

2019 ◽  
Vol 11 (8) ◽  
pp. 688-702 ◽  
Author(s):  
Jiao Wang ◽  
Weihao Li ◽  
Fangfang Zhou ◽  
Ruili Feng ◽  
Fushuai Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Synaptic Plasticity ◽  
Hippocampal Neurons ◽  
Glutamate Release ◽  
Dendritic Morphology ◽  
Receptor Expression ◽  
Hippocampal Synaptic Plasticity ◽  
Synaptic Ultrastructure

Abstract Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders; however, the specific mechanism underlying this process remains unclear. In the present study, abnormal neural and dendritic morphology was observed in the hippocampus following knockout of Atp11b both in vitro and in vivo. Moreover, ATP11B modified synaptic ultrastructure and promoted spine remodeling via the asymmetrical distribution of phosphatidylserine and enhancement of glutamate release, glutamate receptor expression, and intracellular Ca2+ concentration. Furthermore, experimental results also indicate that ATP11B regulated synaptic plasticity in hippocampal neurons through the MAPK14 signaling pathway. In conclusion, our data shed light on the possible mechanisms underlying the regulation of synaptic plasticity and lay the foundation for the exploration of proteins involved in signal transduction during this process.

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

2005 ◽  
Vol 289 (3) ◽  
pp. R656-R662 ◽  
Author(s):  
J. P. Clark ◽  
Christopher S. Sampair ◽  
Paulo Kofuji ◽  
Avindra Nath ◽  
Jian. M. Ding
Keyword(s):  
Nmda Receptor ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Glutamate Release ◽  
Phase Shifts ◽  
Channel Blockers ◽  
Light Entrainment ◽  
Transactivator Of Transcription

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC50= 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-d-aspartate (NMDA) receptor [d-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase ( NG-nitro-l-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 μM), tetanus toxin (1 μM), P/Q/N type-calcium channel blockers (1 μM ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A1(1 μM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.

Evidence for Postsynaptic Induction and Expression of NMDA Receptor Independent LTP

1998 ◽  
Vol 79 (3) ◽  
pp. 1167-1182 ◽  
Author(s):  
Lawrence M. Grover
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Field Potential ◽  
Long Term Potentiation ◽  
Separate Experiment ◽  
Tetanic Stimulation

Grover, Lawrence M. Evidence for postsynaptic induction and expression of NMDA receptor independent LTP. J. Neurophysiol. 79: 1167–1182, 1998. Whole cell/patch-clamp and extracellular field potential recordings were used to study the induction and expression of N-methyl-d-aspartate (NMDA) receptor independent long-term potentiation (LTP) in area CA1 of the in vitro rat hippocampus. Induction of NMDA receptor independent LTP was prevented by manipulations that inhibited postsynaptic depolarization during tetanic stimulation: direct hyperpolarization of postsynaptic neurons and bath application of an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonist. NMDA receptor independent LTP also was blocked by intracellular application of the lidocaine derivative, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), to CA1 pyramidal neurons. These results complement the previous findings that NMDA receptor independent LTP was inhibited by postsynaptic injections of the calcium chelator 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid and also was inhibited by a L-type voltage-dependent calcium channel antagonist (nifedipine). Collectively, these data make a strong case for the postsynaptic induction of this form of LTP. This paper also provides evidence for postsynaptic expression of NMDA receptor independent LTP. In an experiment where AMPA- and NMDA-receptor–mediated excitatory postsynaptic potentials (EPSPs) were isolated pharmacologically, LTP was found for only the AMPA-receptor–mediated EPSPs. In a separate experiment, paired-pulse facilitation (PPF) was measured during NMDA receptor independent LTP. Although there was an initial decrease in PPF, suggesting a posttetanic increase in the probability of glutamate release, the change in PPF decayed within 30–40 min of the tetanic stimulation, whereas the magnitude of the LTP was constant over this same time period. In addition, the LTP, but not the corresponding change in PPF, was blocked by the metabotropic glutamate receptor antagonist (±)-α-methyl-4-carboxyphenylglycine. These results are accounted for most easily by a selective increase in postsynaptic AMPA receptor function, but one type of presynaptic modification—an increase in the number of release sites without an overall change in the probability of release—also could account for these results (assuming that the level of glutamate release before LTP induction fully saturated NMDA, but not AMPA, receptors). One possible presynaptic modification, an increase in axon excitability, was ruled out by analysis of the presynaptic fiber volley, which was not increased at any time after LTP induction.

Modulation of NMDA receptors by prion proteins

2007 ◽  
Vol 30 (4) ◽  
pp. 85
Author(s):  
Houman Khosravani ◽  
Yunfeng Zhang ◽  
Shigeki Tsutsui ◽  
Shahid Hameed ◽  
Jawed Hamid ◽  
...  
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Kainic Acid ◽  
Hippocampal Slices ◽  
Neuronal Cell ◽  
Cellular Prion Protein ◽  
Nmda Receptor Subunits ◽  
Deactivation Kinetics

Background: The precise physiological function of endogenous cellular prion protein (PrPC) remains unclear. It has been shown that PrP-null mice exhibit reduced LTP and greater susceptability to seizure mortality in several in vivo (e.g. kainic acid) models of epilepsy. In addition, PrP-null mice exhibit greater exctitotoxic cell death in response to kainic acid exposure. Methods: In our study we investigated the synaptic properties of WT and PrP-null mice. Results: Recordings in the CA1 layer of adult hippocampal slices showed that PrP-null mice exhibit a reduced threshold to evoked responses and no difference in paired-pulse facilitation relative to WT animals. In addition, greater excitability was observed in PrP-null slices in response to zero-Mg2+ induced seizure-like events. Recordings from mature hippocampal cultures showed slightly altered AMPA and GABAA miniature synaptic currents. NMDA mEPSCs were observed to be increased in amplitude and significantly prolonged in decay time. NMDA-evokved currents also exhibited markedly prolonged deactivation kinetics. This effect on evoked NMDA currents was reproduced in WT neurons by PrP-RNAi transfection, and eliminated by PrPC transfection into PrP-null neurons. Conclusions: These data suggest enhanced NMDA activity in PrP-null neurons. Consistent with this finding, in vitro and in vivo excitotoxicity assays demonstrated increased neuronal cell death in PrP-null cultures and animals upon transient exposure to NMDA. The prolonged deactivation kinetics were most consistent with functional activity/augmentation of NR2D NMDA receptor subunits, and PrP coimmunoprecipiated with NR2D NMDA receptor subunits. This enhanced NMDA receptor function was paralleleld by increased excitotoxicy in Prp-null mice. Our findings demonstrate a novel functional role for PrP as a modulator of synaptic NMDA currents and attributes a neuroprotective function to PrP.

scholarly journals Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Hua Yang ◽  
Mengjie Zhang ◽  
Jiahao Shi ◽  
Yunhe Zhou ◽  
Zhipeng Wan ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Mouse Model ◽  
Glutamate Release ◽  
Critical Role ◽  
Conditional Knockout ◽  
Snare Complex ◽  
Extracellular Glutamate ◽  
Glutamate Level

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

scholarly journals Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin

2010 ◽  
Vol 108 (1) ◽  
pp. 379-384 ◽  
Author(s):  
Shiva K. Tyagarajan ◽  
Himanish Ghosh ◽  
Gonzalo E. Yévenes ◽  
Irina Nikonenko ◽  
Claire Ebeling ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Phosphorylation Site ◽  
Scaffolding Protein ◽  
Scaffolding Proteins ◽  
Gabaergic Synapse ◽  
Gabaergic Synapses

Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca2+-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium.

2.45 GHz microwave radiation impairs learning, memory, and hippocampal synaptic plasticity in the rat

2018 ◽  
Vol 34 (12) ◽  
pp. 873-883 ◽  
Author(s):  
Narges Karimi ◽  
Mahnaz Bayat ◽  
Masoud Haghani ◽  
Hamed Fahandezh Saadi ◽  
Gholam Reza Ghazipour
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Continuous Wave ◽  
Glutamate Release ◽  
Average Power ◽  
Field Potential ◽  
Long Term Potentiation ◽  
Whole Body ◽  
Spatial Learning And Memory ◽  
Hippocampal Synaptic Plasticity

Microwave (MW) radiation has a close relationship with neurobehavioral disorders. Due to the widespread usage of MW radiation, especially in our homes, it is essential to investigate the direct effect of MW radiation on the central nervous system. Therefore, this study was carried out to determine the effect of MW radiation on memory and hippocampal synaptic plasticity. The rats were exposed to 2.45 GHz MW radiation (continuous wave with overall average power density of 0.016 mW/cm2 and overall average whole-body specific absorption rate value of 0.017 W/kg) for 2 h/day over a period of 40 days. Spatial learning and memory were tested by radial maze and passive avoidance tests. We evaluated the synaptic plasticity and hippocampal neuronal cells number by field potential recording and Giemsa staining, respectively. Our results showed that MW radiation exposure decreased the learning and memory performance that was associated with decrement of long-term potentiation induction and excitability of CA1 neurons. However, MW radiation did not have any effects on short-term plasticity and paired-pulse ratio as a good indirect index for measurement of glutamate release probability. The evaluation of hippocampal morphology indicated that the neuronal density in the hippocampal CA1 area was significantly decreased by MW.

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