scholarly journals Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/Ps1 Mice through the GRIP1/AMPA Pathway

2021 ◽  
Author(s):  
Ying Han ◽  
Le Chen ◽  
Jingyun Liu ◽  
Chunyang Wang ◽  
Yu Guo ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Cell Model ◽  
Cytoskeletal Proteins ◽  
Synaptic Proteins ◽  
Human Neuroblastoma ◽  
Transfected Cells ◽  
Related Proteins

Abstract As a neurodegenerative disease, Alzheimer's disease (AD) seriously affects the health of older people. It is now known that changes in synapses occur first in the course of disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) can mediate the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects by using an HDACI, BG45 in Human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/Ps1 transgenic mice during this study. The cells were treated with 15µM BG45 and the APP/Ps1 mice 30mg/kg BG45. We detected the level of synapse-related proteins, HDACs, tau phosphorylation and AMPA receptors by western bloting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA level of GRIK2, SCN3B, SYNPR, Grm2, Grid2IP, GRIP1,GRIP2 were. to explore the effects of HDACi on regulating the synaptic proteins and AMPA receptors. Our studies demonstrated that the expression of HDAC1、HDAC2 and HDAC3 was increased, which was accompanied by the downregulation of the synapse-related proteins synaptophysin (SYP), postsynaptic dendritic protein (PSD-95) and spinophilin as early as 24 h after transfection with APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptotic loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau and increased the level of the synapse-related genes GRIK2, SCN3B, SYNPR, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2 and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. These results suggest that HDACs are involved in the early process of synaptic defects of AD and that BG45 may rescue synaptic damage and loss of hippocampal neurons by specifically inhibiting HDAC1、HDAC2 and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression and finally improving excitatory synapses. BG45 may be considered as a potential drug for the treatment of early AD for further study.

Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons

2001 ◽  
Vol 85 (5) ◽  
pp. 2030-2038 ◽  
Author(s):  
Saobo Lei ◽  
Beverley A. Orser ◽  
Gregory R. L. Thatcher ◽  
James N. Reynolds ◽  
John F. MacDonald
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Organic Nitrate ◽  
Receptor Desensitization ◽  
Open Probability ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Rate Of Recovery ◽  
Kinetics Of

Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC50 of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.

Comparison of the Effects of Convulsant and Depressant Barbiturate Stereoisomers on AMPA-type Glutamate Receptors

1999 ◽  
Vol 90 (6) ◽  
pp. 1704-1713. ◽  
Author(s):  
Yoshinori Kamiya ◽  
Tomio Andoh ◽  
Ryosuke Furuya ◽  
Satoshi Hattori ◽  
Itaru Watanabe ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Dependent Manner ◽  
Induced Current ◽  
Gaba A ◽  
The Central Nervous System

Background Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. Method The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. Results Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. Conclusions Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

scholarly journals GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 715-720 ◽  
Author(s):  
Fabrice Duprat ◽  
Michael Daw ◽  
Wonil Lim ◽  
Graham Collingridge ◽  
John Isaac
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Protein Protein Interactions ◽  
Term Potentiation

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

scholarly journals Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance

2019 ◽  
Author(s):  
Kelly A Jones ◽  
Michiko Sumiya ◽  
Kevin M Woolfrey ◽  
Deepak P Srivastava ◽  
Peter Penzes
Keyword(s):  
Ampa Receptors ◽  
Cortical Neurons ◽  
Glutamate Transporter ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Anterior Cingulate ◽  
Synaptic Proteins ◽  
Inhibitory Synapses ◽  
Nucleotide Exchange

EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras) and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of EPAC2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered of expression of vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT), indicating a potential imbalance in excitatory/inhibitory inputs onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that EPAC2 is required for the correct composition of synapses and that loss of this protein could result in an imbalance of excitatory and inhibitory synapses.

scholarly journals Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

2020 ◽  
Author(s):  
Jithin D. Nair ◽  
Ellen Braksator ◽  
Busra P Yucel ◽  
Richard Seager ◽  
Jack R. Mellor ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Surface Expression ◽  
Receptor Activation ◽  
Kainate Receptors ◽  
Receptor Surface Expression ◽  
Acute Hippocampal Slices

AbstractHere we report that sustained activation of GluK2 subunit-containing kainate receptors leads to AMPA receptor endocytosis and a novel form of long-term depression (KAR-LTDAMPAR) in hippocampal neurons. The KAR-evoked loss of surface AMPA receptors requires KAR channel activity and is occluded by the blockade of PKC or PKA. Moreover, in acute hippocampal slices, kainate invoked LTD of AMPA EPSCs. These data, together with our previously reported KAR-LTPAMPAR, demonstrate that KARs bidirectionally regulate synaptic AMPARs and synaptic plasticity.

d-Serine inhibits AMPA receptor-mediated current in rat hippocampal neurons

2007 ◽  
Vol 85 (5) ◽  
pp. 546-555 ◽  
Author(s):  
Xiang-Qun Gong ◽  
Rebecca L. Zabek ◽  
Donglin Bai
Keyword(s):  
Amino Acids ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Binding Pocket ◽  
Maximal Response ◽  
Competitive Antagonist ◽  
The Right ◽  
Concentration Response Curve ◽  
Native Ligand

d-Serine, a recently identified gliotransmitter, serves as an endogenous coagonist binding to the glycine site of N-methyl-d-aspartate (NMDA) receptors. However, it is not clear whether this native ligand is able to bind to and modulate α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptors. In the present study, we showed that d-serine was able to concentration-dependently inhibit kainate-induced AMPA receptor-mediated current in acutely isolated hippocampal neurons. The blocking action of d-serine on AMPA receptors was characterized by a shift in concentration–response curve of kainate-induced current to the right with no change in the maximal response and independent of holding potential in the range of –80 to +60 mV. This is consistent with a model that d-serine is a competitive antagonist on AMPA receptors. In contrast, l-serine did not exert such an inhibitory action. Consistent with this observation, we found that several d-isoforms, but not l-isoforms, of endogenous and exogenous amino acids were able to block AMPA receptors. These results indicate that there is a low affinity and stereo-selective site at the agonist binding pocket of AMPA receptors for these d-amino acids. More importantly, vesicular-released endogenous d-serine from astrocytes could potentially modulate AMPA receptors in synaptic transmission in hippocampus.

scholarly journals Loss of Depalmitoylation Exaggerates Synaptic Upscaling and Leads to Neuroinflammation in a Lysosomal Storage Disease

2021 ◽  
Author(s):  
Kevin P Koster ◽  
Eden Flores-Barrera ◽  
Emilce Artur de la Villarmois ◽  
Thu T.A. Nguyen ◽  
Amanda Niqula ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Protein Trafficking ◽  
Cortical Neurons ◽  
Microglial Activation ◽  
Storage Disease ◽  
Homeostatic Plasticity ◽  
Synaptic Proteins ◽  
Lysosomal Storage ◽  
Palmitoyl Protein Thioesterase

Palmitoylation and depalmitoylation are the dichotomic processes of lipid modification regulating protein trafficking, recycling, and degradation, thereby controlling proteostasis. Despite our understanding of palmitoylation, depalmitoylation is far less studied. Here, we study a lysosomal depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), associated with the devastating neurodegenerative condition CLN1 disease and show that dark-rearing Ppt1-/- mice, which induces synaptic upscaling in vivo, worsen the symptoms. In Ppt1-/- cortical neurons, upscaling induction triggers exaggerated responses of synaptic calcium-permeable AMPA receptors composed of palmitoylated GluA1 subunits. Consequently, Ppt1-/- visual cortex exhibits hypersynchrony in vivo. Remarkably, we also find an overload of palmitoylated A-kinase anchor protein 5 (Akap5) in Ppt1-/- mouse brains, leading to microglial activation through NFAT. These findings indicate Ppt1 acts as a gatekeeper of homeostatic plasticity by regulating the proteostasis of palmitoylated synaptic proteins. Moreover, our results suggest that perturbed depalmitoylation results in neuroinflammation, which is common to neurodegenerative diseases.

scholarly journals Class I HDAC Inhibitor Improves Synaptic Proteins and Repairs Cytoskeleton Through Regulating Synapse-Related Genes In vitro and In vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Han ◽  
Le Chen ◽  
Yu Guo ◽  
Chunyang Wang ◽  
Chenghong Zhang ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylase Inhibitors ◽  
Early Stage ◽  
Protein Molecule ◽  
Cytoskeletal Proteins ◽  
Synaptic Proteins ◽  
Class I ◽  
Amyloid Aβ

β-amyloid (Aβ) is an important protein molecule in the pathology of Alzheimer’s disease (AD). Accumulation of Aβ leads to the loss of dendritic spines and synapses. These impairments can be ameliorated by histone deacetylase inhibitors (HDACI). However, the mechanisms of HDACIs underlying the effect on synapse are not fully understood. In this study, we examined the relationship between HDAC activity and synapse-related genes and proteins by the administration of a class I HDAC inhibitor, BG45, in the exogenous Aβ-treated cells and mice. Our studies showed that the treatment of HF-488-Aβ1–42 to SH-SY5Y cells first increased the expression of the postsynaptic dendritic protein (PSD), then decreased it after 36 h. BG45 can alleviate the reduction of the expression of PSD-95 as well as spinophilin and cytoskeletal protein induced by HF-488-Aβ1–42 aggregation in SH-SY5Y cells. Similar to the results in vitro, PSD-95 in the hippocampus was temporarily increased in the early days of intravenous injection HF-488-Aβ1–40 to the mice, followed by the decreased expression of PSD-95 on the 9th day. In further studies, for the mice treated with Aβ for 9 days, we found that BG45 decreased the expression of HDAC1 and 2, increased the expression of PSD-95, spinophilin, and synaptophysin (SYP). Our data also showed that BG45 upregulated levels of three synapse-related genes and proteins GRIK2, SCN3B, and SYNPR. These findings suggest that the exogenous Aβ may stimulate transiently the expression of PSD-95 at an early stage, but subsequently contribute to synaptic defects. HDAC1 and 2 are involved in synaptic defects, and BG45 may improve the expression of synaptic and cytoskeletal proteins and repair cytoskeletal damage by specifically inhibiting HDAC1 and 2, thereby modulating synapse-related genes. BG45 might be a potential therapeutic agent for the treatment of an early stage of Aβ-related neurodegenerative disease.

scholarly journals The Effects of Yuan-Zhi Decoction and Its Active Ingredients in Both In Vivo and In Vitro Models of Chronic Cerebral Hypoperfusion by Regulating the Levels of Aβ and Autophagy

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Yan Liu ◽  
Xiaobo Huang ◽  
Wenqiang Chen ◽  
Yujing Chen ◽  
Ningqun Wang ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Hippocampal Neurons ◽  
The Elderly ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Dependent Manner ◽  
Active Ingredients ◽  
Related Proteins

Chronic cerebral hypoperfusion (CCH) is closely related to the occurrence of Alzheimer’s disease (AD) in the elderly. CCH can induce overactivation of autophagy, which increases the deposition of amyloid-β (Aβ) plaques in the brain, eventually impairing the cognitive function. Yuan-Zhi decoction (YZD) is a traditional Chinese medicine (TCM) formulation that is used to treat cognitive dysfunction in the elderly, but the specific mechanism is still unclear. In this study, we simulated CCH in a rat model through bilateral common carotid artery occlusion (BCCAO) and treated the animals with YZD. Standard neurological tests indicated that YZD significantly restored the impaired cognitive function after BCCAO in a dose-dependent manner. Furthermore, YZD also decreased the levels of Aβ aggregates and the autophagy-related proteins ATG5 and ATG12 in their hippocampus. An in vitro model of CCH was also established by exposing primary rat hippocampal neurons to hypoxia and hypoglycemia (H-H). YZD and its active ingredients increased the survival of these neurons and decreased the levels of Aβ1-40 and Aβ1-42, autophagy-related proteins Beclin-1 and LC3-II, and the APP secretases BACE1 and PS-1. Finally, both Aβ aggregates showed a positive statistical correlation with the expression levels of the above proteins. Taken together, YZD targets Aβ, autophagy, and APP-related secretases to protect the neurons from hypoxic-ischemic injury and restore cognitive function.

scholarly journals Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2

2019 ◽  
Vol 29 (12) ◽  
pp. 4919-4931 ◽  
Author(s):  
Dominique Fernandes ◽  
Sandra D Santos ◽  
Ester Coutinho ◽  
Jessica L Whitt ◽  
Nuno Beltrão ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Neuropsychiatric Disorders ◽  
Receptor Function ◽  
Loss Of Function ◽  
Excitatory Transmission ◽  
Morvan’S Syndrome

Abstract Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

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