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1.
Philos Trans R Soc Lond B Biol Sci ; 379(1906): 20230220, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-38853553

ABSTRACT

This review focuses on the activity-dependent diffusion trapping of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as a crucial mechanism for the expression of early long-term potentiation (LTP), a process central to learning and memory. Despite decades of research, the precise mechanisms by which LTP induction leads to an increase in AMPAR responses at synapses have been elusive. We review the different hypotheses that have been put forward to explain the increased AMPAR responsiveness during LTP. We discuss the dynamic nature of AMPAR complexes, including their constant turnover and activity-dependent modifications that affect their synaptic accumulation. We highlight a hypothesis suggesting that AMPARs are diffusively trapped at synapses through activity-dependent interactions with protein-based binding slots in the post-synaptic density (PSD), offering a potential explanation for the increased synaptic strength during LTP. Furthermore, we outline the challenges still to be addressed before we fully understand the functional roles and molecular mechanisms of AMPAR dynamic nanoscale organization in LTP. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.


Subject(s)
Long-Term Potentiation , Receptors, AMPA , Long-Term Potentiation/physiology , Receptors, AMPA/metabolism , Animals , Synapses/physiology , Synapses/metabolism , Diffusion , Humans , Post-Synaptic Density/metabolism
2.
J Neurosci ; 44(23)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38839340

ABSTRACT

A decade ago, in 2013, and over the course of 4 summer months, three separate observations were reported that each shed light independently on a new molecular organization that fundamentally reshaped our perception of excitatory synaptic transmission (Fukata et al., 2013; MacGillavry et al., 2013; Nair et al., 2013). This discovery unveiled an intricate arrangement of AMPA-type glutamate receptors and their principal scaffolding protein PSD-95, at synapses. This breakthrough was made possible, thanks to advanced super-resolution imaging techniques. It fundamentally changed our understanding of excitatory synaptic architecture and paved the way for a brand-new area of research. In this Progressions article, the primary investigators of the nanoscale organization of synapses have come together to chronicle the tale of their discovery. We recount the initial inquiry that prompted our research, the preceding studies that inspired our work, the technical obstacles that were encountered, and the breakthroughs that were made in the subsequent decade in the realm of nanoscale synaptic transmission. We review the new discoveries made possible by the democratization of super-resolution imaging techniques in the field of excitatory synaptic physiology and architecture, first by the extension to other glutamate receptors and to presynaptic proteins and then by the notion of trans-synaptic organization. After describing the organizational modifications occurring in various pathologies, we discuss briefly the latest technical developments made possible by super-resolution imaging and emerging concepts in synaptic physiology.


Subject(s)
Receptors, AMPA , Synapses , Receptors, AMPA/metabolism , Receptors, AMPA/chemistry , Synapses/metabolism , Synapses/ultrastructure , Animals , Humans , Synaptic Transmission/physiology , Nanostructures/chemistry
3.
Article in Russian | MEDLINE | ID: mdl-38884426

ABSTRACT

Depression is a leading cause of disability and reduced work capacity worldwide. The monoamine theory of the pathogenesis of depression has remained dominant for many decades, however, drugs developed on its basis have limited efficacy. Exploring alternative mechanisms underlying this pathology could illuminate new avenues for pharmacological intervention. Targeting glutamatergic pathways in the CNS, particularly through modulation of NMDA and AMPA receptors, demonstrates promising results. This review presents some existing drugs with glutamatergic activity and novel developments based on it to enhance the efficacy of pharmacotherapy for depressive disorders.


Subject(s)
Depressive Disorder , Receptors, AMPA , Receptors, N-Methyl-D-Aspartate , Humans , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, AMPA/metabolism , Depressive Disorder/drug therapy , Depressive Disorder/metabolism , Antidepressive Agents/therapeutic use , Animals
4.
Int J Mol Sci ; 25(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891774

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.


Subject(s)
Amyotrophic Lateral Sclerosis , Glutamic Acid , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Humans , Glutamic Acid/metabolism , Animals , Motor Neurons/metabolism , Motor Neurons/pathology , Aging/metabolism , Receptors, AMPA/metabolism , Endoplasmic Reticulum Stress , Mitochondria/metabolism , Excitatory Amino Acid Transporter 2/metabolism , Astrocytes/metabolism , Reactive Oxygen Species/metabolism
5.
Mol Autism ; 15(1): 28, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38877552

ABSTRACT

BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5-/y rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.


Subject(s)
Disease Models, Animal , Long-Term Potentiation , Protein Serine-Threonine Kinases , Receptors, AMPA , Receptors, N-Methyl-D-Aspartate , Spasms, Infantile , Animals , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, AMPA/metabolism , Receptors, AMPA/genetics , Spasms, Infantile/genetics , Spasms, Infantile/metabolism , Rats , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Hippocampus/metabolism , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Male , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/pathology , CA1 Region, Hippocampal/physiopathology , Epileptic Syndromes/genetics , Epileptic Syndromes/metabolism , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/metabolism , Genetic Diseases, X-Linked/physiopathology , Synapses/metabolism , Excitatory Postsynaptic Potentials
6.
Philos Trans R Soc Lond B Biol Sci ; 379(1906): 20230221, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-38853554

ABSTRACT

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.


Subject(s)
Adiponectin , Dentate Gyrus , Disease Models, Animal , Fragile X Mental Retardation Protein , Fragile X Syndrome , Mice, Knockout , Neuronal Plasticity , Animals , Fragile X Syndrome/physiopathology , Fragile X Syndrome/drug therapy , Fragile X Syndrome/metabolism , Dentate Gyrus/metabolism , Dentate Gyrus/drug effects , Mice , Neuronal Plasticity/drug effects , Fragile X Mental Retardation Protein/metabolism , Fragile X Mental Retardation Protein/genetics , Adiponectin/metabolism , Long-Term Potentiation/drug effects , Male , Receptors, AMPA/metabolism
7.
Philos Trans R Soc Lond B Biol Sci ; 379(1906): 20230240, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-38853555

ABSTRACT

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.


Subject(s)
Gyrus Cinguli , Long-Term Potentiation , Receptors, AMPA , Receptors, N-Methyl-D-Aspartate , Tupaiidae , Animals , Long-Term Potentiation/physiology , Gyrus Cinguli/physiology , Tupaiidae/physiology , Mice , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, AMPA/metabolism , Adenylyl Cyclases/metabolism , Glutamic Acid/metabolism , Male
8.
Mol Brain ; 17(1): 35, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38858726

ABSTRACT

The brain responds to experience through modulation of synaptic transmission, that is synaptic plasticity. An increase in the strength of synaptic transmission is manifested as long-term potentiation (LTP), while a decrease in the strength of synaptic transmission is expressed as long-term depression (LTD). Most of the studies of synaptic plasticity have been carried out by induction via electrophysiological stimulation. It is largely unknown in which behavioural tasks such synaptic plasticity occurs. Moreover, some stimuli can induce both LTP and LTD, thus making it difficult to separately study the different forms of synaptic plasticity. Two studies have shown that an aversive memory task - inhibitory avoidance learning and contextual fear conditioning - physiologically and selectively induce LTP and an LTP-like molecular change, respectively, in the hippocampus in vivo. Here, we show that a non-aversive behavioural task - exploration of new space - physiologically and selectively elicits a biochemical change in the hippocampus that is a hallmark of LTP. Specifically, we found that exploration of new space induces an increase in the phosphorylation of GluA1(Ser831), without affecting the phosphorylation of GluA1(Ser845), which are biomarkers of early-LTP and not NMDAR-mediated LTD. We also show that exploration of new space engenders the phosphorylation of the translational regulator S6K and the expression of Arc, which are features of electrophysiologically-induced late-LTP in the hippocampus. Therefore, our results show that exploration of new space is a novel non-aversive behavioural paradigm that elicits molecular changes in vivo that are analogous to those occurring during early- and late-LTP, but not during NMDAR-mediated LTD.


Subject(s)
Cytoskeletal Proteins , Hippocampus , Long-Term Potentiation , Nerve Tissue Proteins , Receptors, AMPA , Animals , Long-Term Potentiation/physiology , Phosphorylation , Hippocampus/metabolism , Hippocampus/physiology , Receptors, AMPA/metabolism , Male , Nerve Tissue Proteins/metabolism , Cytoskeletal Proteins/metabolism , Exploratory Behavior/physiology , Serine/metabolism
9.
Neurol Neuroimmunol Neuroinflamm ; 11(4): e200254, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38728609

ABSTRACT

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.


Subject(s)
Autoantibodies , CTLA-4 Antigen , Encephalitis , Haploinsufficiency , Hashimoto Disease , Receptors, AMPA , Humans , Male , Child , Encephalitis/diagnosis , Encephalitis/drug therapy , Encephalitis/immunology , Hashimoto Disease/diagnosis , Hashimoto Disease/drug therapy , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Receptors, AMPA/immunology , Rituximab/administration & dosage , Rituximab/therapeutic use , Immunologic Factors
10.
Article in English | MEDLINE | ID: mdl-38692472

ABSTRACT

Stress exposure can lead to post-traumatic stress disorder (PTSD) in male and female rats. Social-Single Prolonged Stress (SPS) protocol has been considered a potential PTSD model. This study aimed to pharmacologically validate the Social-SPS as a PTSD model in male and female rats. Male and female Wistar rats (60-day-old) were exposed to Social-SPS protocol and treated with fluoxetine (10 mg/Kg) or saline solution intraperitoneally 24 h before euthanasia. Two cohorts of animals were used; for cohort 1, male and female rats were still undisturbed until day 7 post-Social-SPS exposure, underwent locomotor and conditioned fear behaviors, and were euthanized on day 9. Animals of cohort 2 were subjected to the same protocol but were re-exposed to contextual fear behavior on day 14. Results showed that fluoxetine-treated rats gained less body weight than control and Social-SPS in both sexes. Social-SPS effectively increased the freezing time in male and female rats on day eight but not on day fourteen. Fluoxetine blocked the increase of freezing in male and female rats on day 8. Different mechanisms for fear behavior were observed in males, such as Social-SPS increased levels of glucocorticoid receptors and Beclin-1 in the amygdala. Social-SPS was shown to increase the levels of NMDA2A, GluR-1, PSD-95, and CAMKII in the amygdala of female rats. No alterations were observed in the amygdala of rats on day fourteen. The study revealed that Social-SPS is a potential PTSD protocol applicable to both male and female rats.


Subject(s)
Amygdala , Fear , Fluoxetine , Rats, Wistar , Stress, Psychological , Animals , Male , Female , Fear/drug effects , Fear/physiology , Fluoxetine/pharmacology , Amygdala/drug effects , Amygdala/metabolism , Stress, Psychological/metabolism , Rats , Disease Models, Animal , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/psychology , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Disks Large Homolog 4 Protein , Receptors, AMPA
11.
Neuroscience ; 549: 42-54, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38729599

ABSTRACT

Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.


Subject(s)
Acetylcysteine , Brain-Derived Neurotrophic Factor , Depression , Inflammation , Lipopolysaccharides , Mice, Inbred C57BL , Neuronal Plasticity , Animals , Male , Depression/drug therapy , Depression/etiology , Depression/metabolism , Depression/prevention & control , Acetylcysteine/pharmacology , Mice , Brain-Derived Neurotrophic Factor/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Neuronal Plasticity/drug effects , Receptors, AMPA/metabolism , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Synaptic Transmission/drug effects , Behavior, Animal/drug effects , Disease Models, Animal , Neurons/drug effects , Neurons/metabolism
12.
ACS Chem Neurosci ; 15(11): 2334-2349, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38747411

ABSTRACT

Parkinson's disease (PD) is a significant health issue because it gradually damages the nervous system. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play a significant role in the development of PD. The current investigation employed hybrid benzodioxole-propanamide (BDZ-P) compounds to get information on AMPA receptors, analyze their biochemical and biophysical properties, and assess their neuroprotective effects. Examining the biophysical characteristics of all the subunits of the AMPA receptor offers insights into the impact of BDZ-P on the desensitization and deactivation rate. It demonstrates a partial improvement in the locomotor capacities in a mouse model of Parkinson's disease. In addition, the in vivo experiment assessed the locomotor activity by utilizing the open-field test. Our findings demonstrated that BDZ-P7 stands out with its remarkable potency, inhibiting the GluA2 subunit nearly 8-fold with an IC50 of 3.03 µM, GluA1/2 by 7.5-fold with an IC50 of 3.14 µM, GluA2/3 by nearly 7-fold with an IC50 of 3.19 µM, and GluA1 by 6.5-fold with an IC50 of 3.2 µM, significantly impacting the desensitization and deactivation rate of the AMPA receptor. BDZ-P7 showed an in vivo impact of partially reinstating locomotor abilities in a mouse model of PD. The results above suggest that the BDZ-P7 compounds show great promise as top contenders for the development of novel neuroprotective therapies.


Subject(s)
Neuroprotective Agents , Receptors, AMPA , Receptors, AMPA/metabolism , Receptors, AMPA/drug effects , Animals , Neuroprotective Agents/pharmacology , Mice , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Mice, Inbred C57BL , Male , Humans , Disease Models, Animal
13.
Biochem Biophys Res Commun ; 722: 150074, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-38805785

ABSTRACT

Genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome enhances the extinction of contextual fear memory, which is attributed to its role in neuronal and synaptic dysregulation, concurrent with neurotransmitter function disturbances. This study aimed to determine whether NLRP3 plays a role in generalizing fear via the inflammatory axis. We established the NLRP3 KO mice model, followed by behavioral and biochemical analyses. The NLRP3 KO mice displayed impaired fear generalization, lower neuroinflammation levels, and dysregulated neurotransmitter function. Additionally, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not the inhibition of NMDA or 5-HT2C receptors, resulted in fear generalization in NLRP3 KO mice because TAT-GluA2 3Y, but not SB242084 and D-cycloserine, treated blocked NLRP3 deprivation effects on fear generalization. Thus, global knockout of NLRP3 is associated with aberrant fear generalization, possibly through AMPA receptor signaling.


Subject(s)
Fear , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Receptors, AMPA , Animals , Fear/physiology , Receptors, AMPA/metabolism , Receptors, AMPA/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , Mice , Male
14.
Hippocampus ; 34(7): 342-356, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38780087

ABSTRACT

Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.


Subject(s)
Dentate Gyrus , Rats, Wistar , Receptors, AMPA , Receptors, N-Methyl-D-Aspartate , Sucrose , Animals , Male , Receptors, AMPA/metabolism , Receptors, AMPA/antagonists & inhibitors , Sucrose/administration & dosage , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Excitatory Amino Acid Antagonists/pharmacology , Proto-Oncogene Proteins c-fos/metabolism , Rats , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Memory/physiology , Memory/drug effects , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Discrimination, Psychological/drug effects , Discrimination, Psychological/physiology , Self Administration , RNA, Messenger/metabolism , Discrimination Learning/drug effects , Discrimination Learning/physiology
15.
Cancer Lett ; 593: 216925, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38718887

ABSTRACT

Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in cancer,but how APA functions in tumorigenesis remains elusive. We analyzed APA events in RNA-seq data in TCGA and reported 3'UTR alterations associated with esophageal squamous cell carcinoma (ESCC) patient prognosis and gene expression changes involving loss of tumor-suppressive miRNA binding sites. Moreover, we investigated the expression and function of cleavage and polyadenylation specific factor 3 (CPSF3), a key APA regulator in ESCC. By immunohistochemistry and qRT-PCR, we found that CPSF3 was highly expressed in ESCC tissues and associated with poor patient prognosis. Overexpression of CPSF3 enhanced, while knockdown of CPSF3 inhibited ESCC cell proliferation and migration in vitro and in vivo, as determined by colony formation, transwell assays and animal experiments. Iso-Seq and RNA-seq data analysis indicated that knockdown of CPSF3 favored use of the distal poly (A) site in the 3'UTR of Cornichon family AMPA receptor auxiliary protein 2 (CNIH2), resulting in a long-3'UTR CNIH2 isoform that produced less CNIH2 protein due to miR-125a-5p targeting and downregulating CNIH2 mRNA through a miR-125a-5p binding site in the long CNIH2 mRNA 3'UTR. Moreover, CPSF3-induced ESCC tumorigenicity was mediated by CNIH2. Taken together, CPSF3 promotes ESCC progression by upregulating CNIH2 expression through loss of miR-125a-5p-mediated CNIH2 repression through alternative splicing and polyadenylation of the CNIH2 mRNA 3'UTR.


Subject(s)
Cell Proliferation , Cleavage And Polyadenylation Specificity Factor , Disease Progression , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Gene Expression Regulation, Neoplastic , Polyadenylation , Animals , Female , Humans , Male , Mice , 3' Untranslated Regions , Cell Line, Tumor , Cell Movement , Cleavage And Polyadenylation Specificity Factor/genetics , Cleavage And Polyadenylation Specificity Factor/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Mice, Nude , MicroRNAs/genetics , MicroRNAs/metabolism , Prognosis , Receptors, AMPA/genetics , Receptors, AMPA/metabolism
16.
Mol Pain ; 20: 17448069241258110, 2024.
Article in English | MEDLINE | ID: mdl-38744422

ABSTRACT

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.


Subject(s)
Adenylyl Cyclases , Colforsin , Gyrus Cinguli , Long-Term Potentiation , Animals , Mice , Gyrus Cinguli/drug effects , Gyrus Cinguli/metabolism , Colforsin/pharmacology , Long-Term Potentiation/drug effects , Adenylyl Cyclases/metabolism , Male , Receptors, AMPA/metabolism , Mice, Inbred C57BL , Synapses/drug effects , Synapses/metabolism , Calcium/metabolism
17.
Methods Cell Biol ; 187: 57-72, 2024.
Article in English | MEDLINE | ID: mdl-38705630

ABSTRACT

Correlative light and electron microscopy (CLEM) can provide valuable information about a biological sample by giving information on the specific localization of a molecule of interest within an ultrastructural context. In this work, we describe a simple CLEM method to obtain high-resolution images of neurotransmitter receptor distribution in synapses by electron microscopy (EM). We use hippocampal organotypic slices from a previously reported mouse model expressing a modified AMPA receptor (AMPAR) subunit that binds biotin at the surface (Getz et al., 2022). This tag can be recognized by StreptAvidin-Fluoronanogold™ conjugates (SA-FNG), which reach receptors at synapses (synaptic cleft is 50-100nm thick). By using pre-embedding labeling, we found that SA-FNG reliably bind synaptic receptors and penetrate around 10-15µm in depth in live tissue. However, the silver enhancement was only reaching the surface of the slices. We show that permeabilization with triton is highly effective at increasing the in depth-gold amplification and that the membrane integrity is well preserved. Finally, we also apply high-resolution electron tomography, thus providing important information about the 3D organization of surface AMPA receptors in synapses at the nanoscale.


Subject(s)
Hippocampus , Receptors, AMPA , Synapses , Animals , Mice , Hippocampus/metabolism , Hippocampus/cytology , Receptors, AMPA/metabolism , Synapses/metabolism , Synapses/ultrastructure , Membrane Proteins/metabolism , Gold/chemistry , Microscopy, Electron/methods , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism
18.
Int Immunopharmacol ; 133: 112080, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38613882

ABSTRACT

Myocardial infarction leads to myocardial inflammation and apoptosis, which are crucial factors leading to heart failure and cardiovascular dysfunction, eventually resulting in death. While the inhibition of AMPA receptors mitigates inflammation and tissue apoptosis, the effectiveness of this inhibition in the pathophysiological processes of myocardial infarction remains unclear. This study investigated the role of AMPA receptor inhibition in myocardial infarction and elucidated the underlying mechanisms. This study established a myocardial infarction model by ligating the left anterior descending branch of the coronary artery in Sprague-Dawley rats. The findings suggested that injecting the AMPA receptor antagonist NBQX into myocardial infarction rats effectively alleviated cardiac inflammation, myocardial necrosis, and apoptosis and improved their cardiac contractile function. Conversely, injecting the AMPA receptor agonist CX546 into infarcted rats exacerbated the symptoms and tissue damage, as reflected by histopathology. This agonist also stimulated the TLR4/NF-κB pathway, further deteriorating cardiac function. Furthermore, the investigations revealed that AMPA receptor inhibition hindered the nuclear translocation of P65, blocking its downstream signaling pathway and attenuating tissue inflammation. In summary, this study affirmed the potential of AMPA receptor inhibition in countering inflammation and tissue apoptosis after myocardial infarction, making it a promising therapeutic target for mitigating myocardial infarction.


Subject(s)
Apoptosis , Myocardial Infarction , Receptors, AMPA , Signal Transduction , Animals , Humans , Male , Rats , Apoptosis/drug effects , Disease Models, Animal , Inflammation/drug therapy , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Myocardial Infarction/metabolism , Myocardium/pathology , Myocardium/metabolism , NF-kappa B/metabolism , Rats, Sprague-Dawley , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/metabolism , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/antagonists & inhibitors
19.
Sci Signal ; 17(834): eadj6603, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38687825

ABSTRACT

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.


Subject(s)
Hippocampus , Intracellular Signaling Peptides and Proteins , Neuronal Plasticity , Phosphoproteins , Protein Serine-Threonine Kinases , Receptors, AMPA , Animals , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Male , Humans , Receptors, AMPA/metabolism , Receptors, AMPA/genetics , Mice , Neuronal Plasticity/physiology , Hippocampus/metabolism , Hippo Signaling Pathway , Serine-Threonine Kinase 3 , Signal Transduction , Memory/physiology , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/genetics , Hepatocyte Growth Factor/metabolism , Mice, Inbred C57BL , Alzheimer Disease/metabolism , Phosphorylation , Neurons/metabolism
20.
J Cell Sci ; 137(8)2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38668720

ABSTRACT

Amyloid ß (Aß) is a central contributor to neuronal damage and cognitive impairment in Alzheimer's disease (AD). Aß disrupts AMPA receptor-mediated synaptic plasticity, a key factor in early AD progression. Numerous studies propose that Aß oligomers hinder synaptic plasticity, particularly long-term potentiation (LTP), by disrupting GluA1 (encoded by GRIA1) function, although the precise mechanism remains unclear. In this study, we demonstrate that Aß mediates the accumulation of GM1 ganglioside in lipid raft domains of cultured cells, and GluA1 exhibits preferential localization in lipid rafts via direct binding to GM1. Aß enhances the raft localization of GluA1 by increasing GM1 in these areas. Additionally, chemical LTP stimulation induces lipid raft-dependent GluA1 internalization in Aß-treated neurons, resulting in reduced cell surface and postsynaptic expression of GluA1. Consistent with this, disrupting lipid rafts and GluA1 localization in rafts rescues Aß-mediated suppression of hippocampal LTP. These findings unveil a novel functional deficit in GluA1 trafficking induced by Aß, providing new insights into the mechanism underlying AD-associated cognitive dysfunction.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Hippocampus , Long-Term Potentiation , Membrane Microdomains , Receptors, AMPA , Amyloid beta-Peptides/metabolism , Receptors, AMPA/metabolism , Membrane Microdomains/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Hippocampus/metabolism , G(M1) Ganglioside/metabolism , Humans , Neurons/metabolism , Rats , Mice , Protein Transport
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