RESUMO
Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.
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Whether or not nonavian dinosaur biodiversity declined prior to the end-Cretaceous mass extinction remains controversial as the result of sampling biases in the fossil record, differences in the analytical approaches used, and the rarity of high-precision geochronological dating of dinosaur fossils. Using magnetostratigraphy, cyclostratigraphy, and biostratigraphy, we establish a high-resolution geochronological framework for the fossil-rich Late Cretaceous sedimentary sequence in the Shanyang Basin of central China. We have found only three dinosaurian eggshell taxa (Macroolithus yaotunensis, Elongatoolithus elongatus, and Stromatoolithus pinglingensis) representing two clades (Oviraptoridae and Hadrosauridae) in sediments deposited between â¼68.2 and â¼66.4 million y ago, indicating sustained low dinosaur biodiversity, and that assessment is consistent with the known skeletal remains in the Shanyang and surrounding basins of central China. Along with the dinosaur eggshell records from eastern and southern China, we find a decline in dinosaur biodiversity from the Campanian to the Maastrichtian. Our results support a long-term decline in global dinosaur biodiversity prior to 66 million y ago, which likely set the stage for the end-Cretaceous nonavian dinosaur mass extinction.
Assuntos
Biodiversidade , Dinossauros , Extinção Biológica , Fósseis , Animais , China , Dinossauros/classificaçãoRESUMO
Distinct molecules are segregated into somatodendritic and axonal compartments of polarized neurons, but mechanisms underlying the development and maintenance of such segregation remain largely unclear. In cultured hippocampal neurons, we observed an ankyrin G- and F-actin-dependent structure that emerged in the cytoplasm of the axon initial segment (AIS) within 2 days after axon/dendrite differentiation, imposing a selective filter for diffusion of macromolecules and transport of vesicular carriers into the axon. Axonal entry was allowed for KIF5-driven carriers of synaptic vesicle protein VAMP2, but not for KIF17-driven carriers of dendrite-targeting NMDA receptor subunit NR2B. Comparisons of transport rates between chimeric forms of KIF17 and KIF5B, with the motor and cargo-binding domains switched, and between KIF5 loaded with VAMP2 versus GluR2 suggest that axonal entry of vesicular carriers depends on the transport efficacy of KIF-cargo complexes. This selective AIS filtering may contribute to preferential trafficking and segregation of cellular components in polarized neurons.
Assuntos
Transporte Axonal , Neurônios/metabolismo , Actinas , Animais , Anquirinas/metabolismo , Axônios/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Citoplasma/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Transferrina/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
Early sensory experiences interact with genes to shape precise neural circuits during development. This process is vital for proper brain function in adulthood. Neurological dysfunctions caused by environmental alterations and/or genetic mutation may share the same molecular or cellular mechanisms. Here, we show that early life bilateral whisker trimming (BWT) subsequently affects social discrimination in adult male mice. Enhanced activation of the hippocampal dorsal CA3 (dCA3) in BWT mice was observed during social preference tests. Optogenetic activation of dCA3 in naive mice impaired social discrimination, whereas chemogenetic silencing of dCA3 rescued social discrimination deficit in BWT mice. Hippocampal oxytocin (OXT) is reduced after whisker trimming. Neonatal intraventricular compensation of OXT relieved dCA3 over-activation and prevented social dysfunction. Neonatal knockdown of OXT receptor in dCA3 mimics the effects of BWT, and cannot be rescued by OXT treatment. Social behavior deficits in a fragile X syndrome mouse model (Fmr1 KO mice) could also be recovered by early life OXT treatment, through negating dCA3 over-activation. Here, a possible avenue to prevent social dysfunction is uncovered.
Assuntos
Síndrome do Cromossomo X Frágil , Ocitocina , Animais , Masculino , Camundongos , Proteína do X Frágil da Deficiência Intelectual , Hipocampo/metabolismo , Ocitocina/farmacologia , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Comportamento SocialRESUMO
CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.
Assuntos
Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Epilepsia Tipo Ausência/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Epilepsia Tipo Ausência/genética , Regulação da Expressão Gênica , Humanos , Mutação , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismoRESUMO
BACKGROUND: To explore the application value of free omental wrapping and modified pancreaticojejunostomy in pancreaticoduodenectomy (PD). METHODS: The clinical data of 175 patients who underwent pancreaticoduodenectomy from January 2015 to December 2020 were retrospectively analysed. In total, 86 cases were divided into Group A (omental wrapping and modified pancreaticojejunostomy) and 89 cases were divided into Group B (control group). The incidences of postoperative pancreatic fistula and other complications were compared between the two groups, and univariate and multivariate logistic regression analyses were used to determine the potential risk factors for postoperative pancreatic fistula. Risk factors associated with postoperative overall survival were identified using Cox regression. RESULTS: The incidences of grade B/C pancreatic fistula, bile leakage, delayed bleeding, and reoperation in Group A were lower than those in Group B, and the differences were statistically significant (P < 0.05). Group A had an earlier drainage tube extubation time, earlier return to normal diet time and shorter postoperative hospital stay than the control group (P < 0.05). The levels of C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) inflammatory factors 1, 3 and 7 days after surgery also showed significant. Univariate and multivariate logistic regression analyses showed that a body mass index (BMI) ≥ 24, pancreatic duct diameter less than 3 mm, no isolation of the greater omental flap and modified pancreaticojejunostomy were independent risk factors for pancreatic fistula (P < 0.05). Cox regression analysis showed that age ≥ 65 years old, body mass index ≥ 24, pancreatic duct diameter less than 3 mm, no isolation of the greater omental flap isolation and modified pancreaticojejunostomy, and malignant postoperative pathology were independent risk factors associated with postoperative overall survival (P < 0.05). CONCLUSIONS: Wrapping and isolating the modified pancreaticojejunostomy with free greater omentum can significantly reduce the incidence of postoperative pancreatic fistula and related complications, inhibit the development of inflammation, and favourably affect prognosis.
Assuntos
Pancreaticoduodenectomia , Pancreaticojejunostomia , Idoso , Humanos , Pancreatectomia/efeitos adversos , Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticojejunostomia/efeitos adversos , Estudos RetrospectivosRESUMO
The N-methyl-D-aspartate receptor (NMDAR) in central nerve system is mostly composed of GluN1 and GluN2 subunits. The classical NMDAR has been intensively studied. However, GluN3containing NMDAR is much less expressed and have atypical channel properties. Recently, accumulating evidences have revealed two types of GluN3containing NMDAR: glutamate-gated GluN1/GluN2/GluN3 NMDAR and glycine-gated GluN1/GluN3 NMDAR. The former may play important roles in regulating synapse maturation and pruning non-used synapses, and its elevated expression at the adult stage may alter synaptic reorganization in some neuropsychiatric disorders. The latter is expressed in the medial habenula and involves in control of aversion. This article reviews the recent progresses on the expression, functional properties of GluN3containing atypical NMDARs and the physiological and pathological relevance.
Assuntos
Sistema Nervoso Central , Receptores de N-Metil-D-Aspartato , Sistema Nervoso Central/metabolismo , Subunidades Proteicas/metabolismo , SinapsesRESUMO
BACKGROUND: Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation. RESULTS: Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice. CONCLUSION: The ROS/PARP/TRPM2 signaling is critical in SiNPs-induced pulmonary inflammation, providing novel mechanistic insights into NPs-induced lung injury. Our study identifies TRPM2 channel as a new target for the development of preventive and therapeutic strategies to mitigate nanomaterials-induced lung inflammation.
Assuntos
Autofagia/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Nanopartículas/toxicidade , Pneumonia/induzido quimicamente , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade , Canais de Cátion TRPM/metabolismo , Animais , Exposição por Inalação , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pneumonia/metabolismo , Pneumonia/patologia , Transdução de Sinais , Propriedades de SuperfícieRESUMO
More and more evidences support that the abnormality of GABAergic interneurons is associated with autism spectrum disorders (ASD), epilepsy, schizophrenia and other neurodevelopmental disorders. In recent years, numerous drugs have been developed to regulate ion channels and receptors in GABAergic interneurons, including sodium channels and N-methyl-D-aspartate (NMDA) receptors. The activators of Na+ channel can enhance the action potential of GABAergic interneurons by reducing the inactivation of Na+ channel. NMDA receptor, as a potential therapeutic target of ASD, can restore the NMDA function of GABAergic interneurons, which would be used to treat behavioral defects. In addition, there are many ion channels and receptors on GABAergic interneurons related to ASD. This article reviews GABAergic interneurons in the pathogenesis of ASD and the related interventions.
Assuntos
Transtorno do Espectro Autista , Neurônios GABAérgicos , Interneurônios , Neurologia , Potenciais de Ação , Transtorno do Espectro Autista/fisiopatologia , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/patologia , Neurologia/tendências , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
BACKGROUND: Suicide has been one of the leading causes of deaths in the United States. One major cause of suicide is psychiatric stressors. The detection of psychiatric stressors in an at risk population will facilitate the early prevention of suicidal behaviors and suicide. In recent years, the widespread popularity and real-time information sharing flow of social media allow potential early intervention in a large-scale population. However, few automated approaches have been proposed to extract psychiatric stressors from Twitter. The goal of this study was to investigate techniques for recognizing suicide related psychiatric stressors from Twitter using deep learning based methods and transfer learning strategy which leverages an existing annotation dataset from clinical text. METHODS: First, a dataset of suicide-related tweets was collected from Twitter streaming data with a multiple-step pipeline including keyword-based retrieving, filtering and further refining using an automated binary classifier. Specifically, a convolutional neural networks (CNN) based algorithm was used to build the binary classifier. Next, psychiatric stressors were annotated in the suicide-related tweets. The stressor recognition problem is conceptualized as a typical named entity recognition (NER) task and tackled using recurrent neural networks (RNN) based methods. Moreover, to reduce the annotation cost and improve the performance, transfer learning strategy was adopted by leveraging existing annotation from clinical text. RESULTS & CONCLUSIONS: To our best knowledge, this is the first effort to extract psychiatric stressors from Twitter data using deep learning based approaches. Comparison to traditional machine learning algorithms shows the superiority of deep learning based approaches. CNN is leading the performance at identifying suicide-related tweets with a precision of 78% and an F-1 measure of 83%, outperforming Support Vector Machine (SVM), Extra Trees (ET), etc. RNN based psychiatric stressors recognition obtains the best F-1 measure of 53.25% by exact match and 67.94% by inexact match, outperforming Conditional Random Fields (CRF). Moreover, transfer learning from clinical notes for the Twitter corpus outperforms the training with Twitter corpus only with an F-1 measure of 54.9% by exact match. The results indicate the advantages of deep learning based methods for the automated stressors recognition from social media.
Assuntos
Aprendizado Profundo , Mídias Sociais , Estresse Psicológico , Prevenção do Suicídio , Algoritmos , Humanos , Redes Neurais de ComputaçãoRESUMO
OBJECTIVE: To explore the feasibility of intraperitoneal injection of isoproterenol (ISO) to induce cardiac remodeling in FVB/N mice. METHODS: Forty-eight FVB/N mice were divided into back subcutaneous saline group (subcutaneous saline group), intraperitoneal saline group, back subcutaneous ISO group (subcutaneous ISO group), and intraperitoneal ISO group according to the route of administration of saline or ISO. ISO (30 µg/g body weight/day) was given to the subcutaneous ISO group and the intraperitoneal ISO group, twice daily with an interval of 12 hours, for 14 consecutive days. The subcutaneous saline group and the intraperitoneal saline group were injected with an equal volume of saline. The left ventricular end-diastolic posterior wall thickness was measured by echocardiography, and the ratio of heart weight to tibia length was determined. Hematoxylin-eosin staining was used to determine the myocardial fiber diameter. Picric-sirius red staining was used to determine the myocardial collagen deposition area. Quantitative real-time PCR was used to measure the mRNA expression of collagen I. RESULTS: Compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups, the intraperitoneal ISO group had increased sizes of the cardiac cavity and the heart. Compared with the subcutaneous saline and intraperitoneal saline groups, the subcutaneous ISO group showed no significant changes in the gross morphology of the cardiac cavity and the heart. The intraperitoneal ISO group showed significant increases in the ratio of heart weight to tibia length, myocardial fiber diameter, left ventricular end-diastolic posterior wall thickness, myocardial collagen area percentage, and the mRNA expression of collagen I compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups (P<0.01). There were no significant differences in the above five indices between the subcutaneous ISO group and the subcutaneous saline and intraperitoneal saline groups (P>0.05). No significant difference in the mortality rate was found between the subcutaneous ISO and intraperitoneal ISO groups (P>0.05). CONCLUSIONS: Intraperitoneal injection of ISO can induce cardiac hypertrophy and fibrosis in FVB/N mice.
Assuntos
Remodelamento Atrial/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Isoproterenol/administração & dosagem , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Colágeno/metabolismo , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
Long term synaptic plasticity, such as long term potentiation (LTP), has been widely accepted as a cellular mechanism underlying memory. Recently, it has been unraveled that Shp2 plays a role in synaptic plasticity and memory in Drosophila and mice, revealing significant and conserved effects of Shp2 in cognitive function. However, the exact mechanism underlying this function of Shp2 in synaptic plasticity and memory still remains elusive. Here, we examine the regulation of Shp2 in hippocampal LTP and contextual fear conditioning. We find that Shp2 is rapidly recruited into spines after LTP induction. Furthermore, the phosphorylation level of Shp2 at Tyr-542 is elevated after LTP stimuli either in cultured hippocampal neurons or acute slices. Notably, contextual fear conditioning also regulates the phosphorylation level of Shp2 at Tyr-542, suggesting fine-tuned regulation of Shp2 in LTP and memory formation. By using a Shp2-specific inhibitor and adeno-associated virus-Cre mediated Shp2 knock-out in cultured neurons, we provide evidence that the phosphatase activity of Shp2 is critical for activity-dependent AMPA receptor surface trafficking. Collectively, our results have revealed a regulatory mechanism of Shp2 underlying LTP and memory, broadening our understanding of Shp2 in cognitive function.
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Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neurônios/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores de AMPA/metabolismo , Animais , Cognição/fisiologia , Drosophila melanogaster , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Camundongos , Neurônios/citologia , Transporte Proteico/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/genéticaRESUMO
The number and subunit composition of synaptic N-methyl-d-aspartate receptors (NMDARs) play critical roles in synaptic plasticity, learning, and memory and are implicated in neurological disorders. Tyrosine phosphorylation provides a powerful means of regulating NMDAR function, but the underling mechanism remains elusive. In this study we identified a tyrosine site on the GluN2B subunit, Tyr-1070, which was phosphorylated by a proto-oncogene tyrosine-protein (Fyn) kinase and critical for the surface expression of GluN2B-containing NMDARs. The phosphorylation of GluN2B at Tyr-1070 was required for binding of Fyn kinase to GluN2B, which up-regulated the phosphorylation of GluN2B at Tyr-1472. Moreover, our results revealed that the phosphorylation change of GluN2B at Tyr-1070 accompanied the Tyr-1472 phosphorylation and Fyn associated with GluN2B in synaptic plasticity induced by both chemical and contextual fear learning. Taken together, our findings provide a new mechanism for regulating the surface expression of NMDARs with implications for synaptic plasticity.
Assuntos
Regulação da Expressão Gênica/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Sinapses/metabolismo , Animais , Camundongos , Camundongos Knockout , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-fyn/genética , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Sinapses/genética , Tirosina/genética , Tirosina/metabolismoRESUMO
N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.
Assuntos
Actinas/fisiologia , Plasticidade Neuronal , Miosina não Muscular Tipo IIB/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Ativação Enzimática , Hipocampo/fisiologia , Técnicas In Vitro , Camundongos , Camundongos Knockout , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , Proteína Quinase C/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-DawleyRESUMO
Ischemia/reperfusion (I/R) injury is the main cause of tissue damage and dysfunction. I/R injury is characterized by Ca(2+) overload and production of reactive oxygen species (ROS), which play critical roles in the process of I/R injury to the brain, heart and kidney, but the underlying mechanisms are largely elusive. Recent evidence demonstrates that TRPM2, a Ca(2+)-permeable cationic channel and ROS sensor, is involved in I/R injury, but whether TRPM2 plays a protective or detrimental role in this process remains controversial. In this review, we discuss the recent progress in understanding the role of TRPM2 in reperfusion process after brain, heart and kidney ischemia and the potential of targeting TRPM2 for the development of therapeutic drugs to treat I/R injury.
Assuntos
Traumatismo por Reperfusão/metabolismo , Canais de Cátion TRPM/fisiologia , Animais , Isquemia Encefálica/metabolismo , Humanos , Rim/irrigação sanguínea , Traumatismo por Reperfusão Miocárdica/metabolismoRESUMO
In the CNS, synapse formation and maturation play crucial roles in the construction and consolidation of neuronal circuits. Neurexin and neuroligin localize on the opposite sides of synaptic membrane and interact with each other to promote the assembly and specialization of synapses. However, the excitatory synapses induced by the neurexin-neuroligin complex are initially immature synapses that lack AMPA receptors. Previously, PICK1 (protein interacting with C kinase 1) was shown to cluster and regulate the synaptic localization of AMPA receptors. Here, we report that during synaptogenesis induced by neurexin in cultured neurons from rat hippocampus, PICK1 recruited AMPA receptors to immature postsynaptic sites. This synaptic recruitment of AMPA receptors depended on the interaction between GluA2 and PICK1, and on the lipid-binding ability of PICK1, but not the interaction between PICK1 and neuroligin. Last, our results demonstrated that the recruitment of GluA2 to synapses could be prevented by ICA69 (islet cell autoantigen 69 kDa), a key binding partner of PICK1. Our study showed that PICK1, being negatively regulated by ICA69, could facilitate synapse maturation.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas Nucleares/metabolismo , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/fisiologia , Receptores de AMPA/metabolismo , Receptores de Superfície Celular/metabolismo , Recrutamento Neurofisiológico/fisiologia , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Células COS , Proteínas de Transporte/genética , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Chlorocebus aethiops , Técnicas de Cocultura , Proteínas do Citoesqueleto , Expressão Gênica , Hipocampo/fisiologia , Mutação , Neurônios/fisiologia , Proteínas Nucleares/genética , Ratos , Ratos Transgênicos , Receptores de Superfície Celular/genética , Recrutamento Neurofisiológico/genéticaRESUMO
Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.
Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Neuralgia/patologia , Receptores de AMPA/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Neuralgia/fisiopatologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Picrotoxina/farmacologia , Receptores de AMPA/genética , Bloqueadores dos Canais de Sódio/farmacologia , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Tetrodotoxina/farmacologiaRESUMO
Polycystic kidney disease-like (PKDL) genes that are expressed in sour taste cells have been proposed to be involved in the transduction of sourness by producing off-responses, which shows a large inward current after withdrawing the acid stimuli. However, the underlying mechanisms of off-responses are still unclear. Here, we demonstrate that an alkali-activated mechanism is responsible for eliciting off-responses, as evidenced by both experimental and theoretical analyses. In addition, we showed that the decaying phase of offset responses in PKD2L1/PKD1L3 channels was substantially accelerated by extracellular Ca(2+).
Assuntos
Canais de Cálcio/química , Ativação do Canal Iônico , Canais Iônicos/química , Receptores de Superfície Celular/química , Álcalis/metabolismo , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Células HEK293 , Humanos , Canais Iônicos/metabolismo , Ligação Proteica , Receptores de Superfície Celular/metabolismoRESUMO
BACKGROUND: Subarachnoid hemorrhage caused by a ruptured intracranial aneurysm (RIA) is a devastating condition with significant morbidity and mortality. Despite the fact that RIAs can be prevented by microsurgical clipping or endovascular coiling, there are no reliable means of effectively predicting IA patients at risk for rupture. The purpose of our study was to discover differentially-expressed glycoproteins in IAs with or without rupture as potential biomarkers to predict rupture. METHODS: Forty age/gender-matched patients with RIA, unruptured IA (UIA), healthy controls (HCs) and disease controls (DCs) (discovery cohort, n = 10 per group) were recruited and a multiplex quantitative proteomic method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), was used to quantify relative changes in the lectin-purified glycoproteins in CSF from RIAs and UIAs compared to HCs and DCs. Then we verified the proteomic results in an independent set of samples (validation cohort, n = 20 per group) by enzyme-linked immunosorbent assay. Finally, we evaluated the specificity and sensitivity of the candidate marker with receiver operating characteristic (ROC) curve methods. RESULTS: The proteomic findings identified 294 proteins, 40 of which displayed quantitative changes unique to RIA, 13 to UIA, and 20 to IA. One of these proteins, receptor tyrosine kinase Axl, was significantly increased in RIA, as confirmed in CSF from the discovery cohort as well as in CSF and plasma from the validation cohort (p <0.05). Spearman's correlation analysis revealed that the CSF and plasma Axl levels were strongly correlated (r = 0.93, p <0.0001). The ROC curve indicated an optimal CSF Axl threshold of 0.12 nM for discriminating RIA from UIA with corresponding sensitivity/specificity of 73.33%/90% and an area under the curve (AUC) of 0.89 (95% CI: 0.80-0.97, p < 0.0001). The optimal threshold for plasma Axl was 1.7 nM with corresponding sensitivity/specificity of 50%/80% and an AUC of 0.71 (95% CI: 0.54-0.87, p = 0.027). CONCLUSIONS: Both CSF and plasma Axl levels are significantly elevated in RIA patients. Axl might serve as a promising biomarker to predict the rupture of IA.