Morphological changes in perisynaptic astrocytes induced by dopamine neuronal degeneration in the striatum of rats.

Introduction: The typical functionality of astrocytes was previously shown to be disrupted by Parkinson's disease (PD), which actively regulates synaptic neurotransmission. However, the morphological changes in astrocytes wrapping glutamatergic synapses in the striatum after dopamine (DA) neuronal degeneration is unclear. Methods: We utilized a range of methodologies, encompassing the 6-hydroxydopamine (6OHDA)-induced PD model, as well as techniques such as immunohistochemistry, Western blotting, immunofluorescence and immunoelectron microscopy (IEM) to delve into the consequences of DA neuronal degeneration on the morphological attributes of perisynaptic astrocytes. Results: Our findings demonstrated a notable rise in glial fibrillary acidic protein (GFAP) + astrocyte density and an upregulation in GFAP protein expression within the striatum due to DA neuronal degeneration, coincided with the enlargement, elongation, and thickening of astrocyte protuberances. However, the expression levels of glutamate transporter 1 (GLT1) and glutamine synthetase (GS), which are related to glutamate-glutamine cycle, were significantly reduced. Double immunofluorescence and IEM results indicated that different proportions of vesicular glutamate transporter 1 (VGlut1)+ and vesicular glutamate transporter 2 (VGlut2) + terminals were wrapped by astrocytes. Additionally, DA neuronal degeneration increased the percentage and area of VGlut1+ and VGlut2+ terminals wrapped by GFAP + astrocytes in the striatum. Furthermore, we noted that DA neuronal degeneration increased the percentage of VGlut1+ and VGlut2+ axo-spinous synapses wrapped by astrocytes but had no effect on axo-dendritic synapses. Conclusion: Hence, perisynaptic astrocytes wrapping striatal glutamatergic synapses exhibit substantial morphological and functional alterations following DA neuronal degeneration making them a potential target for therapeutic interventions in PD.

Lateral hypothalamus orexinergic projection to the medial prefrontal cortex modulates chronic stress-induced anhedonia but not anxiety and despair.

Chronic stress-induced anxiodepression is a common health problem, however its potential neurocircuitry mechanism remains unclear. We used behavioral, patch-clamp electrophysiology, chemogenetic, and optogenetic approaches to clarify the response of the lateral hypothalamus (LH) and the medial prefrontal cortex (mPFC) to stress, confirmed the structural connections between the LH and mPFC, and investigated the role of the LH-mPFC pathway in chronic stress-induced anxiodepression symptoms. Unpredictable chronic mild stress (UCMS) caused anxiodepression-like behaviors, including anxiety, anhedonia, and despair behaviors. We discovered that the activity of the LH and mPFC was both increased after restraint stress (RS), a stressor of UCMS. Then we found that the orexinergic neurons in the LH predominantly project to the glutamatergic neurons in the mPFC, and the excitability of these neurons were increased after UCMS. In addition, overactivated LH orexinergic terminals in the mPFC induced anhedonia but not anxiety and despair behaviors in naive mice. Moreover, chemogenetically inhibited LH-mPFC orexinergic projection neurons and blocked the orexin receptors in the mPFC alleviated anhedonia but not anxiety and despair behaviors in UCMS-treated mice. Our study identified a new neurocircuit from LH orexinergic neurons to mPFC and revealed its role in regulating anhedonia in response to stress. Overactivation of LHOrx-mPFC pathway selectively mediated chronic stress-induced anhedonia. In normal mice, the LHOrx-mPFC pathway exhibits relatively low activity. However, after chronic stress, the activity of orexinergic neuron in LH is overactivated, leading to an increased release of orexin into the mPFC. This heightened orexin concentration results in increased excitability of the mPFC through OX1R and OX2R, consequently triggering anhedonia.

Mediodorsal thalamus projection to medial prefrontal cortical mediates social defeat stress-induced depression-like behaviors.

Clinical studies have shown that the mediodorsal thalamus (MD) may play an important role in the development of depression. However, the molecular and circuit mechanisms by which the mediodorsal thalamus (MD) participates in the pathological processes of depression remain unclear. Here, we show that in male chronic social defeat stress (CSDS) mice, the calcium signaling activity of glutamatergic neurons in MD is reduced. By combining conventional neurotracer and transneuronal virus tracing techniques, we identify a synaptic circuit connecting MD and medial prefrontal cortex (mPFC) in the mouse. Brain slice electrophysiology and fiber optic recordings reveal that the reduced activity of MD glutamatergic neurons leads to an excitatory-inhibitory imbalance of pyramidal neurons in mPFC. Furthermore, activation of MD glutamatergic neurons restores the electrophysiological properties abnormal in mPFC. Optogenetic activation of the MD-mPFC circuit ameliorates anxiety and depression-like behaviors in CSDS mice. Taken together, these data support the critical role of MD-mPFC circuit on CSDS-induced depression-like behavior and provide a potential mechanistic explanation for depression.

Early energy performance analysis of smart buildings by consolidated artificial neural network paradigms.

The assessment of energy performance in smart buildings has emerged as a prominent area of research driven by the increasing energy consumption trends worldwide. Analyzing the attributes of buildings using optimized machine learning models has been a highly effective approach for estimating the cooling load (CL) and heating load (HL) of the buildings. In this study, an artificial neural network (ANN) is used as the basic predictor that undergoes optimization using five metaheuristic algorithms, namely coati optimization algorithm (COA), gazelle optimization algorithm (GOA), incomprehensible but intelligible-in-time logics (IbIL), osprey optimization algorithm (OOA), and sooty tern optimization algorithm (STOA) to predict the CL and HL of a residential building. The models are trained and tested via an Energy Efficiency dataset (downloaded from UCI Repository). A score-based ranking system is built upon three accuracy evaluators including mean absolute percentage error (MAPE), root mean square error (RMSE), and percentage-Pearson correlation coefficient (PPCC) to compare the prediction accuracy of the models. Referring to the results, all models demonstrated high accuracy (e.g., PPCCs >89%) for predicting both CL and HL. However, the calculated final scores of the models (43, 20, 39, 38, and 10 in HL prediction and 36, 20, 42, 42, and 10 in CL prediction for the STOA, OOA, IbIL, GOA, and COA, respectively) indicated that the GOA, IbIL, and STOA perform better than COA and OOA. Moreover, a comparison with various algorithms used in earlier literature showed that the GOA, IbIL, and STOA provide a more accurate solution. Therefore, the use of ANN optimized by these three algorithms is recommended for practical early forecast of energy performance in buildings and optimizing the design of energy systems.

Effects of DeSUMOylated Spastin on AMPA Receptor Surface Delivery and Synaptic Function Are Enhanced by Phosphorylating at Ser210.

Surface trafficking of AMPA receptors (AMPARs) is one of the important mechanisms mediating synaptic plasticity which is essential for cognitive functions such as learning and memory. Spastin, as a novel binding partner for the AMPAR, has been reported to regulate AMPAR surface expression and synaptic function. Additionally, Spastin undergoes two posttranslational modifications, phosphorylation and SUMOylation, both of which are crucial for synaptic function. However, gaps exist in our knowledge of how Spastin phosphorylation cross-talks with its SUMOylation in the regulation of AMPAR surface expression and synaptic function. Here, we reported that deSUMOylation of Spastin at Lys427 increased the surface level of AMPAR GluA2 subunit, the amplitude and frequency of miniature excitatory synaptic currents (mEPSC), and facilitated the morphological maturation of dendritic spines in cultured hippocampal neurons. Further studies demonstrated that Spastin phosphorylation at Ser210 further increased the enhancement of GluA2 surface expression and synaptic function by deSUMOylated Spastin, while dephosphorylation had the opposite effect. Simultaneously, deSUMOylation at Lys427 significantly increased the promoting effect of Spastin phosphorylation on synaptic function. In conclusion, our study suggests that cooperative interactions between phosphorylated and deSUMOylated Spastin are novel pathways to enhance synaptic function.

Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis.

Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer's disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice's spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.

Enriched environment ameliorates learning and memory deficits in hepatic encephalopathy mice by restoration of the structure of dendrites and dendritic spines.

Cognitive impairment is one of the most common symptoms of hepatic encephalopathy (HE). However, there is a lack of easily implementable rehabilitation strategies. As an easy-to-implement strategy, numerous studies suggest that enriched environment (EE) can be beneficial for cognitive function. However, the effects of EE on learning and memory, as well as dendritic spines plasticity in HE is still unclear. Accordingly, in the present study, we evaluated the effects of EE on the behavior and dendritic spine morphology in an animal model of HE. Our results showed that HE mice have no movement disorder and anxiety, but they exhibit spatial learning and memory dysfunction. Further analysis revealed that the complexity of the dendrites and the maturity of the dendritic spines are reduced in the hippocampus of HE mice. After 4 weeks of housekeeping in EE, dendritic complexity, and dendritic spine maturity, as well as the spatial learning and memory function of HE mice were restored. In conclusion, exposure to EE can positively influence dendritic spines plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions in HE.

Association between ABO blood groups and postoperative pain in children after adenotonsillectomy: a prospective cohort study.

BACKGROUND: It has been known that ABO blood groups are linked to the phenotypes of certain diseases; however, and the relationship between ABO blood groups and postoperative pain have not been extensively studied, especially in children. This study was to investigate whether there would be an association between the four major ABO blood groups and postoperative pain, as indicated by the differences in pain scores and rescue fentanyl requirements among blood groups in children after adenotonsillectomy. METHODS: A total of 124 children, aged 3-7 years, ASA I or II, and undergoing elective adenotonsillectomy were enrolled in the study. Postoperative pain was evaluated using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and the rescue fentanyl requirement in post anesthesia care unit (PACU) was analyzed. Pediatric Anesthesia Emergence Delirium (PAED) score and the duration of PACU were recorded. The postoperative nausea and vomiting (PONV) within 24 h were documented. RESULTS: Among four blood type groups, no significant differences were observed regarding surgery time, and the gaps of fentanyl given at the anesthesia induction and the first rescue fentanyl injection in PACU. However, patients from AB and B blood groups had significantly higher pain score at initial CHEOPS assessment and consequently, higher consumption of rescue fentanyl during PACU stay. A significantly higher percentage of patients had received > 1 µg/kg rescue fentanyl. Higher PAED scores were also observed in AB and B blood groups. CONCLUSION: Paediatric patients with AB and B blood type had higher postoperative CHEOPS pain score and required significantly more fentanyl for pain control than those with A and O blood type after T&A. The initial scores of PAED in patients with AB and B blood type were also higher than that in patients with A and O blood type.

Social defeat drives hyperexcitation of the piriform cortex to induce learning and memory impairment but not mood-related disorders in mice.

Clinical studies have shown that social defeat is an important cause of mood-related disorders, accompanied by learning and memory impairment in humans. The mechanism of mood-related disorders has been widely studied. However, the specific neural network involved in learning and memory impairment caused by social defeat remains unclear. In this study, behavioral test results showed that the mice induced both learning and memory impairments and mood-related disorders after exposure to chronic social defeat stress (CSDS). c-Fos immunofluorescence and fiber photometry recording confirmed that CaMKIIα expressing neurons of the piriform cortex (PC) were selectively activated by exposure to CSDS. Next, chemogenetics and optogenetics were performed to activate PC CaMKIIα expressing neurons, which showed learning and memory impairment but not mood-related disorders. Furthermore, chemogenetic inhibition of PC CaMKIIα expressing neurons significantly alleviated learning and memory impairment induced by exposure to CSDS but did not relieve mood-related disorders. Therefore, our data suggest that the overactivation of PC CaMKIIα expressing neurons mediates CSDS-induced learning and memory impairment, but not mood-related disorders, and provides a potential therapeutic target for learning and memory impairment induced by social defeat.

Impaired learning and memory generated by hyperthyroidism is rescued by restoration of AMPA and NMDA receptors function.

Hyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.

The use of a surgical boot camp combining anatomical education and surgical simulation for internship preparedness among senior medical students.

BACKGROUND: Senior medical students feel unprepared for surgical procedures and care for surgery patients when they begin their internship. This study sought to introduce and evaluate a surgical boot camp training for senior medical students. METHODS: A 44-h surgical boot camp program of lectures on clinical practice simulation, anatomical dissections, and simulated operation on cadavers was designed, implemented, and evaluated during the 2018 to 2019 academic year. A self-administered questionnaire was used to assess students' perceptions of the content, delivery, and self-confidence. The mini-Clinical Evaluation Exercise (mini-CEX) and the Operative Performance Rating System were used to assess skills essential to good clinical care and to facilitate feedback. RESULTS: Over 93% of the students were satisfied with the surgical boot camp, training equipment, and learning materials provided. After six sessions of training, 85.3% reported gaining self-confidence and performed better in some surgical procedures such as major gastrectomy. The mini-CEX scores suggested significant improvement in the students' clinical skills, attitudes, and behaviors (P < 0.01). Ninety-eight percent of students felt that the anatomical knowledge taught met their needs. The scores of the Operative Performance Rating System suggested that the students' surgical skills such as instruments handling, incising, treatment of surrounding tissues (blood vessels, nerves), and smoothness of the whole operation had increased significantly following the surgical boot camp (All P < 0.01). CONCLUSION: The surgical boot camp curriculum improved students' satisfaction and confidence in core clinical practice competencies. Therefore, medical schools the world over should continue to seek ways to bridge the gaps between pre-clinical, clinical, and internship training.

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches.

Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 µM). The SPR assay demonstrates that CGA can directly bind to GluA1 (KD = 496 µM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is -39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1-CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.

Medical students' perceptions and performance in an online regional anatomy course during the Covid-19 pandemic.

The present study evaluated the students' psychological well-being, experiences, performance, and perception of learning regional anatomy remotely. A regional anatomy remote learning curriculum was designed and learning materials were delivered virtually to 120 undergraduate medical students at Jinan University, China. All the students consented and voluntarily participated in this study by completing self-administered online questionnaires including the Zung's Self-Rating Anxiety and Depression Scales at the beginning and end of the learning session. A subset participated in focus group discussions. Most of the students (90.0%) positively evaluated the current distance learning model. More than 80% were satisfied with the content arrangement and coverage. Many students preferred virtual lectures (68.2%) and videos showing dissections (70.6%) during the distance learning sessions. However, writing laboratory reports and case-based learning were the least preferred modes of learning as they were only preferred by 23.2% and 14.1% of the students, respectively. There was no significant lockdown-related anxiety or depression reported by students using depression and anxiety scales as well as feedback from focus group discussions. The surveyed students' confidence scores in distance learning were significantly higher after 5 weeks than at the beginning of the session (3.05 ± 0.83 vs. 3.70 ± 0.71, P < 0.05). Furthermore, the present results showed no significant differences between the current group's academic performance in the unit tests as well as the final overall evaluation for different parts of the course compared to that of the previous year's cohort. The findings above were congruent with focus group discussion data that the use of the online teaching platform for regional anatomy significantly improved the students' confidence in virtual and self-directed learning and did not negatively affect their academic performance.

Comprehensive Analysis of lncRNAs, miRNAs and mRNAs in Mouse Hippocampus With Hepatic Encephalopathy.

Hepatic encephalopathy (HE) often presents with varying degrees of cognitive impairment. However, the molecular mechanism of its cognitive impairment has not been fully elucidated. Whole transcriptome analysis of hippocampus between normal and HE mice was performed by using RNA sequencing. 229 lncRNAs, 49 miRNAs and 363 mRNAs were differentially expressed in HE mice. The lncRNA-miRNA-mRNA interaction networks were established, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Dysregulated RNAs in interaction networks were mainly involved in synaptic plasticity and the regulation of learning and memory. In NH4Cl-treated hippocampal neurons, the dendritic spine density and maturity decreased significantly, the amplitude and frequency of mIPSC increased, while the amplitude and frequency of mEPSC decreased. These manifestations can be reversed by silencing SIX3OS1. Further research on these no-coding RNAs may lead to new therapies for the treatment and management of brain dysfunction caused by HE.

Strategies for Targeting Neural Circuits: How to Manipulate Neurons Using Virus Vehicles.

Viral strategies are the leading methods for mapping neural circuits. Viral vehicles combined with genetic tools provide the possibility to visualize entire functional neural networks and monitor and manipulate neural circuit functions by high-resolution cell type- and projection-specific targeting. Optogenetics and chemogenetics drive brain research forward by exploring causal relationships among different brain regions. Viral strategies offer a fresh perspective for the analysis of the structure-function relationship of the neural circuitry. In this review, we summarize current and emerging viral strategies for targeting neural circuits and focus on adeno-associated virus (AAV) vectors.

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors.

Synaptic plasticity is essential for cognitive functions such as learning and memory. One of the mechanisms involved in synaptic plasticity is the dynamic delivery of AMPA receptors (AMPARs) in and out of synapses. Mutations of SPAST, which encodes SPASTIN, a microtubule-severing protein, are considered the most common cause of hereditary spastic paraparesis (HSP). In some cases, patients with HSP also manifest cognitive impairment. In addition, mice with Spastin depletion exhibit working and associative memory deficits and reduced AMPAR levels. However, the exact effect and molecular mechanism of Spastin on AMPARs trafficking has remained unclear. Here, we report that Spastin interacts with AMPAR, and phosphorylation of Spastin enhances its interaction with AMPAR subunit GluA2. Further study shows that phosphorylation of Spastin can increase AMPAR GluA2 surface expression and the amplitude and frequency of miniature excitatory synaptic currents (mEPSC) in cultured hippocampal neurons. Moreover, phosphorylation of Spastin at Ser210 is crucial for GluA2 surface expression. Phosphorylation of Spastin K353A, which obliterates microtubule-severing activity, also promotes AMPAR GluA2 subunit trafficking to the surface and increases the amplitude and frequency of mEPSCs in cultured neurons. Taken together, our data demonstrate that Spastin phosphorylation promotes the surface delivery of the AMPAR GluA2 subunit independent of microtubule dynamics.

Comprehensive analysis of GSEC/miR-101-3p/SNX16/PAPOLG axis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. A growing number of studies have shown that competitive endogenous RNA (ceRNA) regulatory networks might play important roles during HCC process. The present study aimed to identify a regulatory axis of the ceRNA network associated with the development of HCC. The roles of SNX16 and PAPOLG in HCC were comprehensively analyzed using bioinformatics tools. Subsequently, the "mRNA-miRNA-lncRNA" model was then used to predict the upstream miRNAs and lncRNAs of SNX16 and PAPOLG using the miRNet database, and the miRNAs with low expression and good prognosis in HCC and the lncRNAs with high expression and poor prognosis in HCC were screened by differential expression and survival analysis. Finally, the risk-prognosis models of ceRNA network axes were constructed by univariate and multifactorial Cox proportional risk analysis, and the immune correlations of ceRNA network axes were analyzed using the TIMER and GEPIA database. In this study, the relevant ceRNA network axis GSEC/miR-101-3p/SNX16/PAPOLG with HCC prognosis was constructed, in which GSEC, SNX16, and PAPOLG were highly expressed in HCC with poor prognosis, while miR-101-3p was lowly expressed in HCC with good prognosis. The risk-prognosis model predicted AUC of 0.691, 0.623, and 0.626 for patient survival at 1, 3, and 5 years, respectively. Immuno-infiltration analysis suggested that the GSEC/miR-101-3p/SNX16/PAPOLG axis might affect macrophage polarization. The GSEC/miR-101-3p/SNX16/PAPOLG axis of the ceRNA network axis might be an important factor associated with HCC prognosis and immune infiltration.

Phosphorylation of CRMP2 by Cdk5 Negatively Regulates the Surface Delivery and Synaptic Function of AMPA Receptors.

AMPA receptor mediate most fast excitatory synaptic transmission and play a key role in synaptic plasticity in the central nervous system (CNS) by trafficking and targeting of its subunits to individual postsynaptic membrane. Collapsing response mediator protein 2 (CRMP2), an intracellular phospho-protein, has been reported to promote the maturation of the dendritic spine and transfer AMPA receptors to the membrane. However, our knowledge about the molecular mechanisms of CRMP2 regulating AMPA receptors trafficking is limited. Here, we reported that CRMP2 promoted the surface expression of AMPA receptor GluA1 subunit in cultured hippocampal neurons and in HEK293T cells expressing GluA1 subunits. Furthermore, we found that CRMP2 interacted with GluA1, and their interaction was inhibited by CRMP2 phosphorylation at ser522. Moreover, our results showed that phosphorylation of CRMP2 at ser522 by cyclin-dependent kinase 5 (Cdk5) decreased the fluorescence intensity of surface GluA1 and the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) in cultured hippocampal neurons, indicating a reduction levels and synaptic function of AMPA receptors. Taken together, our data demonstrated that phosphorylation of CRMP2 by Cdk5 is important for AMPA receptor surface delivery in hippocampal neurons.

Comparison of the median effective concentration (EC50) and effect of sevoflurane with or without remifentanil in cesarean section with supreme laryngeal mask under narcotrend monitoring: a randomized trial.

BACKGROUND: Remifentanil combined with sevoflurane is a standard protocol for obstetric general anesthesia (GA). METHODS: In this study, we performed a randomized clinical trial to evaluate whether remifentanil has an effect on the median effective concentration (EC50) of sevoflurane and compare anesthetic outcomes of them in cesarean section with Supreme™ laryngeal mask airway (SLMA) under narcotrend monitoring. Ninety parturients with singleton births undergoing elective cesarean delivery (CD) with initial inhaled 1.0 minimum alveolar concentration (MAC) sevoflurane for anesthesia maintenance were assigned to three groups randomly and evenly: Group A (0.05 µg·kg-1·min-1 remifentanil combined with sevoflurane), Group B (0.1 µg·kg-1·min-1 remifentanil combined with sevoflurane), and Group C (normal saline combined with sevoflurane). Narcotrend was used to monitor the depth of anesthesia during the operation, with the level of anesthesia depth controlled within the D-E stage. The EC50 of sevoflurane was determined by Dixon's sequential method. The Narcotrend index, amount of bleeding, neonatal Apgar score, and corresponding treatment measures in the three groups were recorded. RESULTS: The results showed that the estimated EC50 of sevoflurane for obstetric GA was 0.80 MAC (95% CI: 0.63-0.95 MAC) in group A, 0.82 MAC (95% CI: 0.63-0.96 MAC) in group B, and 0.80 MAC (95% CI: 0.63-0.95 MAC) in group C. There was no statistically significant difference in the estimated EC50 of sevoflurane, time to wakefulness, Apgar score, amount of intraoperative bleeding, and postoperative bleeding within 24 hours between the three groups (all P>0.05). CONCLUSIONS: The addition of remifentanil at 0.05-0.1 µg·kg-1·min-1 did not change the EC50 of sevoflurane and anesthetic quality. The concentration of inhaled anesthetics can be minimized with Narcotrend monitoring. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000034512.