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The BAD-BAX-caspase-3 cascade is a canonical apoptosis pathway. Macroautophagy ("autophagy" hereinafter) is a process by which organelles and aggregated proteins are delivered to lysosomes for degradation. Here, we report a new function of the BAD-BAX-caspase-3 cascade and autophagy in the control of synaptic vesicle pools. We found that, in hippocampal neurons of male mice, the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools and influences the kinetics of activity-induced depletion and recovery of synaptic vesicle pools. Moreover, the caspase-autophagy pathway is engaged by fear conditioning to facilitate associative fear learning and memory. This work identifies a new mechanism for controlling synaptic vesicle pools, and a novel, nonapoptotic, presynaptic function of the BAD-BAX-caspase-3 cascade.SIGNIFICANCE STATEMENT Despite the importance of synaptic vesicles for neurons, little is known about how the size of synaptic vesicle pools is maintained under basal conditions and regulated by neural activity. This study identifies a new mechanism for the control of synaptic vesicle pools, and a new, nonapoptotic function of the BAD-BAX-caspase-3 pathway in presynaptic terminals. Additionally, it indicates that autophagy is not only a homeostatic mechanism to maintain the integrity of cells and tissues, but also a process engaged by neural activity to regulate synaptic vesicle pools for optimal synaptic responses, learning, and memory.
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Autofagia/fisiología , Caspasa 3/deficiencia , Transducción de Señal/fisiología , Vesículas Sinápticas/metabolismo , Proteína X Asociada a bcl-2/deficiencia , Proteína Letal Asociada a bcl/deficiencia , Animales , Caspasa 3/genética , Células Cultivadas , Células HEK293 , Humanos , Masculino , Ratones , Ratones Noqueados , Imagen Molecular/métodos , Técnicas de Cultivo de Órganos , Vesículas Sinápticas/genética , Vesículas Sinápticas/ultraestructura , Proteína X Asociada a bcl-2/genética , Proteína Letal Asociada a bcl/genéticaRESUMEN
Catalysis is regarded as an effective strategy to fundamentally increase sulfur utilization, accelerating the kinetics of the transformation between lithium polysulfides (LiPSs) and lithium sulfide (Li2 S) on a substrate. However, the intermodulation of catalysts and sulfur species is elusive, which is limited to the comprehensive analysis of electrochemical performance in the dynamic reaction process. Herein, cobalt nanoparticles loaded on MXene nanosheets (Co/Ti2 C) are selected as sulfur hosts and the representative catalyst. By combining ex situ electrochemical results and interfacial structural chemical monitoring, the catalysis process of Co/Ti2 C toward LiPSs conversion is revealed, and the outstanding performance originates from the optimization of chemical adsorption, catalytic activity, and lithium-ion transfer behaviors, which is based on electronic/ion modulation and sufficient interfaces among catalysts and electrolyte. This work can guide the construction of electronic modulation at triple-phase interface catalysis to overcome the shuttle effect and facilitate sulfur redox kinetics in Li-S batteries.
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Mitochondria are cellular ATP generators. They are dynamic structures undergoing fission and fusion. While much is known about the mitochondrial fission machinery, the mechanism of initiating fission and the significance of fission to neurophysiology are largely unclear. Gamma oscillations are synchronized neural activities that impose a great energy challenge to synapses. The cellular mechanism of fueling gamma oscillations has yet to be defined. Here, we show that dysbindin-1, a protein decreased in the brain of individuals with schizophrenia, is required for neural activity-induced fission by promoting Drp1 oligomerization. This process is engaged by gamma-frequency activities and in turn, supports gamma oscillations. Gamma oscillations and novel object recognition are impaired in dysbindin-1 null mice. These defects can be ameliorated by increasing mitochondrial fission. These findings identify a molecular mechanism for activity-induced mitochondrial fission, a role of mitochondrial fission in gamma oscillations, and mitochondrial fission as a potential target for improving cognitive functions.
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Mitocondrias , Dinámicas Mitocondriales , Animales , Dinaminas , Disbindina , Ratones , Ratones Noqueados , Proteínas Mitocondriales , SinapsisRESUMEN
Heightened aggression can be serious concerns for the individual and society at large and are symptoms of many psychiatric illnesses, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression increase, however, are poorly understood. Here we find that prior attack experience leading to an increase in aggressive behavior, known as aggression priming, activates neurons within the posterior ventral segment of the medial amygdala (MeApv). Optogenetic stimulation of MeApv using a synaptic depression protocol suppresses aggression priming, whereas high-frequency stimulation enhances aggression, mimicking attack experience. Interrogation of the underlying neural circuitry revealed that the MeApv mediates aggression priming via synaptic connections with the ventromedial hypothalamus (VmH) and bed nucleus of the stria terminalis (BNST). These pathways undergo NMDAR-dependent synaptic potentiation after attack. Furthermore, we find that the MeApv-VmH synapses selectively control attack duration, whereas the MeApv-BNST synapses modulate attack frequency, both with no effect on social behavior. Synaptic potentiation of the MeApv-VmH and MeApv-BNST pathways contributes to increased aggression induced by traumatic stress, and weakening synaptic transmission at these synapses blocks the effect of traumatic stress on aggression. These results reveal a circuit and synaptic basis for aggression modulation by experience that can be potentially leveraged toward clinical interventions.SIGNIFICANCE STATEMENT Heightened aggression can have devastating social consequences and may be associated with psychiatric disorders, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression escalation, however, are poorly understood. Here we identify two aggression pathways between the posterior ventral segment of the medial amygdala and its downstream synaptic partners, the ventromedial hypothalamus and bed nucleus of the stria terminalis that undergo synaptic potentiation after attack and traumatic stress to enhance aggression. Notably, weakening synaptic transmission in these circuits blocks aggression priming, naturally occurring aggression, and traumatic stress-induced aggression increase. These results illustrate a circuit and synaptic basis of aggression modulation by experience, which can be potentially targeted for clinical interventions.
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Agresión/fisiología , Complejo Nuclear Corticomedial/fisiología , Vías Nerviosas/fisiología , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Animales , Masculino , Ratones Endogámicos C57BL , Distrés PsicológicoRESUMEN
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene and consequent absence of its protein product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can suppress translation. The absence of FMRP leads to symptoms of FXS including intellectual disability and has been proposed to lead to abnormalities in synaptic plasticity. Synaptic plasticity, protein synthesis, and cellular growth pathways have been studied extensively in hippocampal slices from a mouse model of FXS (Fmr1 KO). Enhanced metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD), increased rates of protein synthesis, and effects on signaling molecules have been reported. These phenotypes were found under amino acid starvation, a condition that has widespread, powerful effects on activation and translation of proteins involved in regulating protein synthesis. We asked if this non-physiological condition could have effects on Fmr1 KO phenotypes reported in hippocampal slices. We performed hippocampal slice experiments in the presence and absence of amino acids. We measured rates of incorporation of a radiolabeled amino acid into protein to determine protein synthesis rates. By means of western blots, we assessed relative levels of total and phosphorylated forms of proteins involved in signaling pathways regulating translation. We measured evoked field potentials in area CA1 to assess the strength of the long-term depression response to mGluR activation. In the absence of amino acids, we replicate many of the reported findings in Fmr1 KO hippocampal slices, but in the more physiological condition of inclusion of amino acids in the medium, we did not find evidence of enhanced mGluR5-dependent LTD. Activation of mGluR5 increased protein synthesis in both wild type and Fmr1 KO. Moreover, mGluR5 activation increased eIF2α phosphorylation and decreased phosphorylation of p70S6k in slices from Fmr1 KO. We propose that the eIF2α response is a cellular attempt to compensate for the lack of regulation of translation by FMRP. Our findings call for a re-examination of the mGluR theory of FXS.
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Aminoácidos/farmacología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Hipocampo/metabolismo , Depresión Sináptica a Largo Plazo/fisiología , Biosíntesis de Proteínas/fisiología , Transducción de Señal/fisiología , Animales , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Hipocampo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Biosíntesis de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Agrin has recently been identified as a novel oncogene that is overexpressed in several types of human cancers. However, its role in lung cancer has not yet been investigated. The purpose of the current study was to investigate agrin protein expression in lung cancer and evaluate its clinicopathological and prognostic significance. In this study, A total of 86 lung adenocarcinoma samples paired with adjacent non-tumour tissue samples and eight lung adenocarcinoma non-paired samples were selected for immunohistochemical staining for agrin. Strong staining of agrin in nuclei of lung adenocarcinoma tissues was observed, but not in the nuclei of normal lung tissues (p < 0.001). Consistent with staining in lung adenocarcinoma tissues, the nuclei staining of agrin was also detected in lung cancer cell lines by immunofluorescence. This is the first report demonstrating that agrin is highly expressed in nuclei of lung adenocarcinoma tissues and that it is strongly correlated with lymph node metastasis (p = 0.002), clinical stage (p = 0.024), and poor differentiation (p = 0.022). Agrin-positive nuclear staining of lung adenocarcinoma cells could be used to identify greatly increased risk of metastasis in patients after surgery, which might serve as a valuable prognostic marker.
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Adenocarcinoma del Pulmón/metabolismo , Agrina/metabolismo , Neoplasias Pulmonares/metabolismo , Biomarcadores de Tumor/metabolismo , Humanos , Metástasis Linfática , Estadificación de Neoplasias , PronósticoRESUMEN
NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior.
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Región CA1 Hipocampal/fisiología , Miedo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Memoria/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Potenciación a Largo Plazo/fisiología , Ratones , Ratones Noqueados , Receptores de N-Metil-D-Aspartato/genética , Proteína X Asociada a bcl-2/genéticaRESUMEN
MXenes, due to their unique geometric structure, rich elemental composition, and intrinsic physicochemical properties, have multi-functional applications. In the field of electrochemical energy storage, MXenes can be used as active components, conductive agents, supports, and catalysts in ion-intercalated batteries, metal-sulfur batteries, and supercapacitors. The electrochemical performance of MXene materials is closely related to their distinctive physical and chemical properties, which depend on their geometry, surface functional groups, and elemental composition. How to regulate MXene materials to optimize electrochemical functions is a key scientific challenge. Herein, we correlated the function of MXene materials with their interlayer structure, surface functional groups, and specific catalytic sites, analyzed the electrochemical function of MXene materials, and showed how to design the electrochemical function of MXene materials based on ion/electron transport. Additionally, this feature article provides an outlook on the opportunities and challenges for MXenes, offering theoretical and technical guidance on using MXene materials in energy storage systems.
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Fluorine owing to its inherently high electronegativity exhibits charge delocalization and ion dissociation capabilities; as a result, there has been an influx of research studies focused on the utilization of fluorides to optimize solid electrolyte interfaces and provide dynamic protection of electrodes to regulate the reaction and function performance of batteries. Nonetheless, the shuttle effect and the sluggish redox reaction kinetics emphasize the potential bottlenecks of lithium-sulfur batteries. Whether fluorine modulation regulate the reaction process of Li-S chemistry? Here, the TiOF/Ti3C2 MXene nanoribbons with a tailored F distribution were constructed via an NH4F fluorinated method. Relying on in situ characterizations and electrochemical analysis, the F activates the catalysis function of Ti metal atoms in the consecutive redox reaction. The positive charge of Ti metal sites is increased due to the formation of O-Ti-F bonds based on the Lewis acid-base mechanism, which contributes to the adsorption of polysulfides, provides more nucleation sites and promotes the cleavage of S-S bonds. This facilitates the deposition of Li2S at lower overpotentials. Additionally, fluorine has the capacity to capture electrons originating from Li2S dissolution due to charge compensation mechanisms. The fluorine modulation strategy holds the promise of guiding the construction of fluorine-based catalysts and facilitating the seamless integration of multiple consecutive heterogeneous catalytic processes.
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How to construct a new electrode/electrolyte interface structure in solid-state batteries (SSBs), enhance interface stability, and improve the cycling performance of SSBs is a great challenge for the development of SSBs. Here, an all-in-one "interface-free" structure was developed. This interfacial structure constructs a full-interface hydrogen bonding network through the abundant hydrogen bond donors and acceptors in the cathode and electrolyte to enhance the interfacial stability and avoid interfacial failure during charging and discharging, and generates cathode-electrolyte interface (CEI) in-situ to effectively regulate zinc ion transport. Square cells assembled in this structure are stabilized for 100 cycles at a current density of 0.1 mA cm-2. This integrated electrode provides a new idea for the long stable cycle of SSBs.
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OBJECTIVES: The objective of this study was to explore the effect of periodontitis on Th-cell subsets in local and systemic environments. METHODS: A total of 32 male Sprague-Dawley rats were randomly divided into periodontitis and control groups. Silk ligatures were applied to the mandibular first (M1) molars in the periodontitis group. Inflammation and alveolar bone loss around the M1 molars were analyzed by histological staining and microcomputed tomography. The mRNA expression of interferon-γ (IFN-γ), interleukin 4 (IL-4), IL-17, and IL-10 in the gingiva was measured by qRT-PCR. The proportions of Th1, Th2, Th17, and Treg cells in the submandibular lymph nodes, peripheral blood, and jaw bone marrow were tested using flow cytometry. RESULTS: More inflammatory cells and alveolar bone resorption were found in the periodontitis group, with upregulated mRNA expression of IFN-γ, IL-17, and IL-10. The proportion of Th1 and Th17 cells was significantly elevated in submandibular lymph nodes, and the proportion of Th1, Th2, and Th17 cells was significantly elevated in peripheral blood, while the proportion of Th1, Th17, and Treg cells was significantly elevated in jaw bone marrow in the periodontitis group. CONCLUSION: This study suggests that periodontitis affects the differentiation of Th-cell subsets in both local and systemic environments, resulting in an increased proportion of proinflammatory cells.
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Pérdida de Hueso Alveolar , Periodontitis , Ratas , Masculino , Animales , Interleucina-10/metabolismo , Citocinas/metabolismo , Interleucina-17/metabolismo , Microtomografía por Rayos X , Ratas Sprague-Dawley , Periodontitis/metabolismo , Interferón gamma , Células Th17 , ARN Mensajero/metabolismoRESUMEN
The mechanism of long-term depression (LTD), a cellular substrate for learning, memory, and behavioral flexibility, is extensively studied in Schaffer collateral (SC) synapses, with inhibition of autophagy identified as a key factor. SC inputs terminate at basal and proximal apical dendrites, whereas distal apical dendrites receive inputs from the temporoammonic pathway (TAP). Here, we demonstrate that TAP and SC synapses have a shared LTD mechanism reliant on NMDA receptors, caspase-3, and autophagy inhibition. Despite this shared LTD mechanism, proximal apical dendrites contain more autophagosomes than distal apical dendrites. Additionally, unlike SC LTD, which diminishes with age, TAP LTD persists into adulthood. Our previous study shows that the high autophagy in adulthood disallows SC LTD induction. The reduction of autophagosomes from proximal to distal dendrites, combined with distinct LTD inducibility at SC and TAP synapses, suggests a model where the differential distribution of autophagosomes in dendrites gates LTD inducibility at specific circuits.
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Autofagosomas , Dendritas , Hipocampo , Depresión Sináptica a Largo Plazo , Sinapsis , Dendritas/fisiología , Sinapsis/fisiología , Autofagosomas/fisiología , Animales , Ratones , Receptores de N-Metil-D-Aspartato/metabolismo , Caspasa 3/metabolismo , Autofagia , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Ratones Endogámicos C57BL , Hipocampo/citología , Hipocampo/fisiología , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Lithium-sulfur (Li-S) batteries, as one of the new energy storage batteries, show immense potential due to their high theoretical specific capacity and theoretical energy density. However, there are still some problems to be solved, among which the shuttle effect of lithium polysulfides is one extremely serious issue with respect to the industrial application of Li-S batteries. Rational design of electrode materials with effective catalytic conversion ability is an effective route to accelerate the conversion of lithium polysulfides (LiPSs). Herein, considering the adsorption and catalysis of LiPSs, CoOx nanoparticles (NPs) loaded on carbon sphere composites (CoOx/CS) were designed and constructed as cathode materials. The CoOx NPs obtained, with ultralow weight ratio and uniform distribution, consist of CoO, Co3O4, and metallic Co. The polar CoO and Co3O4 enable chemical adsorption towards LiPSs through Co-S coordination, and the conductive metallic Co can improve electronic conductivity and reduce impedance, which is beneficial for ion diffusion at the cathode. Based on these synergistic effects, the CoOx/CS electrode exhibits accelerated redox kinetics and enhanced catalytic activity for conversion of LiPSs. Consequently, the CoOx/CS cathode delivers improved cycling performance, with an initial capacity of 980.8 mA h g-1 at 0.1C and a reversible specific capacity of 408.4 mA h g-1 after 200 cycles, along with enhanced rate performance. This work provides a facile route to construct cobalt-based catalytic electrodes for Li-S batteries, and promotes understanding of the LiPSs conversion mechanism.
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BACKGROUND: The odontogenic jaw cyst is a cavity containing liquid, semifluid or gaseous components, with the development of the disease. In recent years, with the rapid development of oral materials and the transformation of treatment of jaw cysts, more options are available for treatment of postoperative bone defect of jaw cysts. Guided bone regeneration (GBR) places biomaterials in the bone defect, and then uses biofilm to separate the proliferative soft tissue and the slow-growing bone tissue to maintain the space for bone regeneration, which is widely used in the field of implantology. AIM: To observe the clinical effect of GBR in repairing bone defect after enucleation of small and medium-sized odontogenic jaw cysts. METHODS: From June 2018 to September 2020, 13 patients (7 male, 6 female) with odontogenic jaw cysts were treated in the Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Adults without hypertension, heart disease, diabetes or other systemic diseases were selected. The diagnosis was based on the final pathological results: 11 cases were diagnosed as apical cysts, one as primordial cyst, and one as dentigerous cyst. The lesions were located in the maxilla in seven cases, and in the mandible in six cases. All cases were treated with the same method of enucleation combined with GBR. RESULTS: Three to four months after the operation, the boundary between the implant site and the surrounding normal stroma was not obvious in patients with small-sized odontogenic jaw cysts. The patients with tooth defects were treated with implant after 6 mo. For the patients with medium-sized odontogenic jaw cysts, the density of the center of the implant area was close to the normal mass at 6 mo after surgery, and there was a clear boundary between the periphery of the implant area and the normal mass. The boundary between the periphery of the implant area and the normal mass was blurred at 8-9 mo after surgery. Patients with tooth defects were treated with implants at > 6 mo after the operation. CONCLUSION: Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts can shorten the time of osteogenesis, increase the amount of new bone formation, reduce complications, and improve quality of life.
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BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.
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Espinas Dendríticas , Dinámicas Mitocondriales , Adenosina Trifosfato , Animales , Espinas Dendríticas/metabolismo , GTP Fosfohidrolasas/metabolismo , Ratones , Proteínas Mitocondriales/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Psychosocial stress is a common risk factor for anxiety disorders. The cellular mechanism for the anxiogenic effect of psychosocial stress is largely unclear. Here, we show that chronic social defeat (CSD) stress in mice causes mitochondrial impairment, which triggers the PINK1-Parkin mitophagy pathway selectively in the amygdala. This mitophagy elevation causes excessive mitochondrial elimination and consequent mitochondrial deficiency. Mitochondrial deficiency in the basolateral amygdalae (BLA) causes weakening of synaptic transmission in the BLA-BNST (bed nucleus of the stria terminalis) anxiolytic pathway and increased anxiety. The CSD-induced increase in anxiety-like behaviors is abolished in Pink1-/- and Park2-/- mice and alleviated by optogenetic activation of the BLA-BNST synapse. This study identifies an unsuspected role of mitophagy in psychogenetic-stress-induced anxiety elevation and reveals that mitochondrial deficiency is sufficient to increase anxiety and underlies the psychosocial-stress-induced anxiety increase. Mitochondria and mitophagy, therefore, can be potentially targeted to ameliorate anxiety.
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Complejo Nuclear Basolateral , Mitofagia , Animales , Ansiedad , Trastornos de Ansiedad , Complejo Nuclear Basolateral/metabolismo , Ratones , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold.
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Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Hipocampo/fisiología , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
Although an increasing number of studies have demonstrated the plasticity of NMDA receptor-mediated synaptic transmission, little is known about the molecular mechanisms that underlie this neurologically important process. In a study of NMDAR-mediated synaptic responses in hippocampal Schaffer-CA1 synapses whose AMPA receptor (AMPAR) activity is totally blocked, we uncovered differences between the trafficking mechanisms that underlie the long-term potentiation (LTP) and long-term depression (LTD) that can be induced in these cells under these conditions. The LTP-producing protocol failed to induce a change in the amplitude of NMDAR-mediated postsynaptic currents (NMDAR EPSCs) in the first 5-10 min, but induced gradual enhancement of NMDAR EPSCs thereafter that soon reached a stable magnitude. This "slow" LTP of NMDAR EPSCs (LTP(NMDA)) was blocked by inhibiting exocytosis or actin polymerization in postsynaptic cells. By contrast, LTD of NMDAR EPSCs (LTD(NMDA)) was immediately inducible, and, although it was blocked by the actin stabilizer, it was unaffected by exocytosis or endocytosis inhibitors. Furthermore, concomitant changes in the decay time of NMDAR EPSCs suggested that differential switches in NR2 subunit composition accompanied LTP(NMDA) and LTD(NMDA), and these changes were blocked by the calcium buffer BAPTA or an mGluR antagonist. Our results suggest that LTP(NMDA) and LTD(NMDA) utilize different NMDAR trafficking pathways and express different ratios of NMDAR subunits on the postsynaptic surface.
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Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Análisis de Varianza , Animales , Biofisica , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Interacciones Farmacológicas , Estimulación Eléctrica , Endocitosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Exocitosis/efectos de los fármacos , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Técnicas de Placa-Clamp/métodos , Faloidina/farmacología , Piperidinas/farmacología , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Toxina Tetánica/farmacología , Tiazolidinas/farmacologíaRESUMEN
NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity. Its expression is mediated by the removal of AMPA receptors from postsynaptic membranes. Under basal conditions, endocytosed AMPA receptors are rapidly recycled back to the plasma membrane. In NMDAR-LTD, however, they are diverted to late endosomes for degradation. The mechanism for this switch is largely unclear. Additionally, the inducibility of NMDAR-LTD is greatly reduced in adulthood. The underlying mechanism and physiological significance of this phenomenon are elusive. Here, we report that autophagy inhibition is essential for the induction and developmental dampening of NMDAR-LTD. Autophagy is inhibited during NMDAR-LTD to decrease endocytic recycling. Autophagy inhibition is both necessary and sufficient for LTD induction. In adulthood, autophagy is up-regulated to make LTD induction harder, thereby preventing the adverse effect of excessive LTD on memory consolidation. These findings reveal the unrecognized functions of autophagy in synaptic plasticity, endocytic recycling, and memory.
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Autofagia/fisiología , Endocitosis/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Animales , Autofagia/genética , Células Cultivadas , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/fisiología , Técnicas de Cultivo de TejidosRESUMEN
Lateral diffusion of glutamate receptors was proposed as a mechanism for regulating receptor numbers at synapses and affecting synaptic functions, especially the efficiency of synaptic transmission. However, a direct link between receptor lateral diffusion and change in synaptic function has not yet been established. In the present study, we demonstrated NMDA receptor (NMDAR) lateral diffusion in CA1 neurons in hippocampal slices by detecting considerable recovery of spontaneous or evoked EPSCs from the block of (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], an irreversible NMDAR open-channel blocker. We observed changes on both the number and the composition of synaptic NMDAR on recovery. More importantly, after the recovery, long-term potentiation (LTP)-producing protocol induced only LTD (long-term depression) instead of LTP. In contrast, a complete recovery from competitive NMDAR blocker D,L-AP-5 was observed without subsequent changes on synaptic plasticity. Our data suggest a revised model of NMDAR trafficking wherein extrasynaptic NMDARs, mostly NR1/NR2B receptors, move laterally into synaptic sites, resulting in altered rule of synaptic modification. Thus, CA1 synapses exhibit a novel form of metaplasticity in which the direction of synaptic modification can be reverted through subtype-specific lateral diffusion of NMDA receptors.