Transcriptome and metabolome analyses revealed the response mechanism of pepper roots to Phytophthora capsici infection.

BACKGROUND: Phytophthora root rot caused by the oomycete Phytophthora capsici is the most devastating disease in pepper production worldwide, and current management strategies have not been effective in preventing this disease. Therefore, the use of resistant varieties was regarded as an important part of disease management of P. capsici. However, our knowledge of the molecular mechanisms underlying the defense response of pepper roots to P. capsici infection is limited. METHODS: A comprehensive transcriptome and metabolome approaches were used to dissect the molecular response of pepper to P. capsici infection in the resistant genotype A204 and the susceptible genotype A198 at 0, 24 and 48 hours post-inoculation (hpi). RESULTS: More genes and metabolites were induced at 24 hpi in A204 than A198, suggesting the prompt activation of defense responses in the resistant genotype, which can attribute two proteases, subtilisin-like protease and xylem cysteine proteinase 1, involved in pathogen recognition and signal transduction in A204. Further analysis indicated that the resistant genotype responded to P. capsici with fine regulation by the Ca2+- and salicylic acid-mediated signaling pathways, and then activation of downstream defense responses, including cell wall reinforcement and defense-related genes expression and metabolites accumulation. Among them, differentially expressed genes and differentially accumulated metabolites involved in the flavonoid biosynthesis pathways were uniquely activated in the resistant genotype A204 at 24 hpi, indicating a significant role of the flavonoid biosynthesis pathways in pepper resistance to P. capsici. CONCLUSION: The candidate transcripts may provide genetic resources that may be useful in the improvement of Phytophthora root rot-resistant characters of pepper. In addition, the model proposed in this study provides new insight into the defense response against P. capsici in pepper, and enhance our current understanding of the interaction of pepper-P. capsici.

Biosensors and biomarkers for determining gestational diabetes mellitus and jaundice in children.

Gestational diabetes and jaundice are the correlated diseases predominantly found in mother and newborn child. Jaundice is a neonatal complication with an increased risk when mother has gestational diabetes. Mothers with diabetes at an early stage of gestational age are at higher risk for hyperbilirubinemia (jaundice) and hypoglycemia. So, it is mandatory to monitor the condition of diabetes and jaundice during the pregnancy period for a healthy child and safest delivery. On the other hand, nanotechnology has displayed a rapid advancement that can be implemented to overcome these issues. The development of high-performance diagnosis using appropriate biomarkers provides their efficacy in the detection gestational diabetes and jaundice. This review covers the aspects from a fast-developing field to generate nanosensors in the nanosized dimensions for the applications to overcome these complications by coupling diagnostics with biomarkers. Further, the serum-based biomarkers have been discussed for these inborn complications and also the diagnosis with the current trend.

Electrical lesion of bilateral ventrolateral orbital cortex impairs fear- and space-related learning and affects subsequent choice behavior.

OBJECTIVES: Although many studies have indicated that orbitofrontal cortex plays an important role in the learning and retrieval of memory and subsequent decision-making, the role of ventrolateral orbital cortex (VLO) still remains unclear, especially related to fear and space. METHODS: Four separate cohorts of rats were used in this study. After sham surgery and electrical lesion of bilateral VLO, four cohorts received active avoidance test, passive avoidance test, Morris water maze and T maze separately. RESULTS: Firstly, data shown that electrolytic lesions of bilateral VLO of Sprague-Dawley rats shortened the latency of rats to escape to darkroom in passive avoidance test. Besides, the damage of VLO also resulted in decrease of the number of active avoidance of rats from the third day during 5 consecutive days' training in active avoidance test. What's more, the impairment of VLO significantly shortened the exploring time in the target quadrant of rats in Morris water maze. Furthermore, VLO-lesions group shown lower correct alternation percentage than sham group in T maze. CONCLUSIONS: These results indicated that not only in the learning and retrieval of fear-related memory, VLO also plays an important role in the learning and retrieval of spatial-related memory guided by visual cues.

Rapid migration of mainland China's coastal erosion vulnerability due to anthropogenic changes.

With the global rise in sea levels caused by climate change and frequent extreme weather processes, high-density population aggregation and human development activities to enhance coastal areas vulnerability, populations, resources, and the ecological environment are facing huge pressure. Natural coastlines are being destroyed, and increasingly serious problems, such as coastal erosion and ecological fragility, have become disasters in coastal zones. The coastal vulnerability changed by climatic variables has created a major concern at regional, national and global scales. By comparing the data of two periods in the past 40 years, coastline vulnerability of coastal erosion in mainland China were evaluated by use of reverse cloud model and AHP with 10 indicators, including natural, anthropogenic, social and economic factors, etc. The main factors controlling coastal erosion included the proportion of Quaternary strata, the gradual reclamation of marine areas as land areas (in kilometres) and the percentage decrease in coastal sediment entering the sea. The secondary impact factors included the high proportion of artificial coastlines and the impacts of waves and storm surges under the influence of relative sea level changes. Human activities could further influence coastal vulnerability, making the erosion risk a considerable concern. Legislation, coordinated management system and technology are proposed to improve the quality of the marine ecological environment.

Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats.

BACKGROUND: Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation. RESULTS: Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What's more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats. CONCLUSIONS: These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.

The role of HINT1 protein in morphine addiction: An animal model-based study.

Drug addiction is a recurrent, chronic brain disease. The existing treatment methods have limitations, such as poor adherence and inability to completely avoid relapse. Histidine triad nucleotide-binding protein 1 (HINT1) is involved in many neuropsychiatric diseases, such as schizophrenia, pain, and drug dependence. Studies have confirmed that there is a genetic link between HINT1 and addictions such as nicotine and cocaine. However, there is no research on the role of HINT1 protein in morphine addiction at home and abroad. Thus, we designed this project by constructing different types of morphine addiction animal models, including conditioned place preference and behavioral sensitization. We comprehensively examined the participation of HINT1 protein in key brain regions associated with addiction, including prefrontal cortex, nucleus accumbens, corpus striatum, and hippocampus, in different stages of different models. In addition, we used HINT1 knockout mice to establish the above models and physical dependence model to investigate the effect of HINT1 protein deletion on morphine addiction-related behaviors. We found that HINT1 has varying degrees of involvement in different stages of multiple addictive animal models. The absence of HINT1 can attenuate morphine-mediated addictive behavior to a certain extent and can alleviate the withdrawal symptoms of morphine.

Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury.

OBJECTIVES: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. DESIGN: Experimental animal study. SETTING: Research laboratory. SUBJECTS: Adult male mice and hippocampal brain slices. INTERVENTIONS: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). MEASUREMENTS AND MAIN RESULTS: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. CONCLUSIONS: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury-induced persistent cognitive deficits.

Challenges for accessing and maintaining good quality of HIV care among men who have sex with men living with HIV in China: a qualitative study with key stakeholders.

HIV care in China is shifting toward a community-based model involving a wide range of stakeholders. We aimed to understand key stakeholders' perceived challenges of providing high-quality care for men who have sex with men (MSM) living with HIV. In-depth interviews were conducted with a diverse sample of stakeholders (N = 17) in two Chinese cities, including providers, policymakers, and community workers. Interviews focused on stakeholders' challenges in HIV-related work and perceived barriers for MSM in accessing and maintaining HIV care. Thematic analysis strategies were used. Three cross-cutting themes related to accessibility and quality of care (QoC) emerged. First, MSM- and HIV-related stigma were perceived to increase the risk of MSM dropping out of care. While acknowledging stigma, some providers also expressed discriminatory views such as stereotypes of the MSM community. Second, stakeholders expressed concerns about QoC including healthcare workforce shortages, limited training opportunities, and high work stress while facing increasingly unmet needs from clients. Third, stakeholders shared challenges in mobilizing community resources to expand HIV care including unclear division of responsibility and strict auditing. Supportive policies and resources may be needed to bolster China's primary care workforce and MSM-competent care and, more broadly, high QoC for sexual and gender minority patients.

Sophocarpine exert protective effect against ox-LDL-induced endothelial damage via regulating NF-κB signaling pathway.

Oxidized low-density lipoprotein (ox-LDL) was known to induce endothelial cell injury to the progression of atherosclerosis (AS). Sophocarpine (SPC), a compound of sophora alkaloids isolated from the plant Sophora alopecuroides, has been shown to exhibit various pharmacological activities. This study was designed to investigate the protective effect of SPC on ox-LDL-induced endothelial cells and explored its underlying mechanism. Our results show that SPC pre-incubation ameliorated ox-LDL-mediated HAECs cytotoxicity, DNA fragmentation, and apoptosis in a dose-dependent manner. Moreover, SPC significantly downregulated the mRNA or protein expression level of pro-inflammatory mediators (TGF-ß, IL-6, IL-1ß, TNF-α) and pro-inflammatory vascular adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Mechanistically, SPC pre-treatment downregulated IκBα expression and inhibited translocation of NF-κB in ox-LDL-mediated HAECs, overexpression of NF-κB p65 counteracted the cytoprotective and anti-apoptotic effect of SPC, suggesting that its action is dependent on NF-κB signaling pathway. Collectively, SPC suppresses ox-LDL-induced HAECs injury by inhibiting the NF-κB signaling pathway.

Multipath TCP-Based IoT Communication Evaluation: From the Perspective of Multipath Management with Machine Learning.

With the development of wireless networking technology, current Internet-of-Things (IoT) devices are equipped with multiple network access interfaces. Multipath TCP (MPTCP) technology can improve the throughput of data transmission. However, traditional MPTCP path management may cause problems such as data confusion and even buffer blockage, which severely reduces transmission performance. This research introduces machine learning algorithms into MPTCP path management, and proposes an automatic learning selection path mechanism based on MPTCP (ALPS-MPTCP), which can adaptively select some high-quality paths and transmit data at the same time. This paper designs a simulation experiment that compares the performance of four machine learning algorithms in judging path quality. The experimental results show that, considering the running time and accuracy, the random forest algorithm has the best performance in judging path quality.

Worldwide tendency and perspectives in traumatic dental injuries: A bibliometric analysis over two decades (1999-2018).

BACKGROUND/AIMS: Traumatic dental injuries (TDIs) are considered to be a public dental health problem worldwide. The aim of the current study was to provide the worldwide tendency and perspectives in TDIs in the last two decades via bibliometric analysis. METHODS: ''Tooth injuries'' was searched as the Medical Subject Headings term within PubMed with the date range from 1999 to 2018. Two investigators perused information in the articles according to the inclusion and exclusion criteria. The articles were independently categorized according to the following aspects: (a) annual scholarly output; (b) leading countries or regions; (c) leading journals; (d) productive authors; (e) citations; (f) study design; (f) distribution of topics; and (g) the type of dentition and TDIs. VOSviewer 1.6.7 and Citespace 5.2 were used for analyzing and visualizing bibliometric networks. RESULTS: A total of 2627 articles about traumatic dental injuries were published and indexed in PubMed during the two decades, and the number of publications on traumatic dental injuries was rising in general. The research outputs were mainly concentrated in developed countries and affiliated hospitals of universities. Brazil was the most productive country. The journal Dental Traumatology had the most contributions to the scientific research of traumatic dental injuries. "Case report" was the most frequent type of article (36.50%), followed by cross-sectional studies (19.57%) and case-control studies (13.67%). Most studies focused on the treatment of TDIs (38.94%), especially for avulsion (21.01%), crown fracture (9.71%), and intrusion (5.25%). Permanent teeth (66%) were the dominant dentition. CONCLUSION: There is a lack of high-quality well-designed studies such as cohort studies. The number of publications on prevention and the primary dentition is disproportionate in relation to their significance.

A Novel Color Modulation Analysis Strategy through Tunable Multiband Laser for Nanoparticle Identification and Evaluation.

Creating color difference and improving the color resolution in digital imaging is crucial for better application of color analysis. Herein, a novel color modulation analysis strategy was developed by using a homemade tunable multiband laser illumination device, in which the portions of R, G, and B components of the illumination light are discretionarily adjustable, and hence the sample color could be visually modulated continuously in the RGB color space. Through this strategy, the color appearance of single gold nanorods (AuNRs) under dark-field microscopy was migrated from the spectrally insensitive red region to the spectrally sensitive green-yellow region. Unlike the traditional continuous-wave light source illumination, wherein the small spectral variations in the samples within a narrow spectral range are averaged by the whole spectrum of the light source, leading to little color difference, the application of sharp, multiband laser illumination could enlarge the color separation between samples, thus resulting in high spectral sensitivity in color analysis. By comparing the corresponding color evolution processes of different samples as the multiband combination of the laser illumination was changed, more efficient color separation of AuNRs was achieved. With this instrument and single Ag@AuNRs as the sulfide probe, we achieved high throughput and highly sensitive detection of sulfide at a detection limit of 0.1 nM, a more than 2 orders of magnitude improvement compared to the previous color sensing scheme. This strategy could be utilized for nanoparticle identification, evaluation, and determination in biological imaging and biochemical analysis.

Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. METHODS: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. RESULTS: The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. CONCLUSIONS: Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

Lysophosphatidic Acid Promotes Expression and Activation of Matrix Metalloproteinase 9 (MMP9) in THP-1 Cells via Toll-Like Receptor 4/Nuclear Factor-κB (TLR4/NF-κB) Signaling Pathway.

BACKGROUND Lysophosphatidic acid (LPA) is an active compound of oxidized low-density lipoprotein that serves as an endogenous TLR4 ligand. Ligand activation of TLR4 activates nuclear factor-kappaB (NF-κB) and the transcription of NF-κB-regulated inflammatory cytokines, which are involved in the development of atherosclerosis. MMP9 is a member of the MMP family and can affect plaque stability. However, the mechanism responsible for the effect of LPA on the expression and activation of MMP9 has not been fully elucidated. In the present study we examined the effect of LPA on MMP9 expression and activity in THP-1 cells and the involvement of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway in this effect. MATERIAL AND METHODS Human THP-1 cells were treated with 0-10 µM LPA for 4 h, or treated with 1 µM LPA for 0-8 h, and were then transfected with TLR4-specific siRNA or treated with 20 µg/ml cafestol acid phenethyl ester (CAPE, an NF-κB inhibitor). MMP9 mRNA and protein levels were measured by quantitative RT-PCR and Western blot analysis, respectively, and MMP9 activity was measured by zymography. RESULTS LPA upregulated MMP9 mRNA and protein levels and MMP9 activity in THP-1 cells in both concentration- and time-dependent manners. Transfection of cells with TLR4-siRNA-2 or treatment with CAPE significantly inhibited the upregulated MMP9 expression and activation. This inhibition was further enhanced by combining the TLR4-siRNA-2 transfection and CAPE pretreatment. CONCLUSIONS LPA can promote MMP9 expression and enhance MMP9 activity in THP-1 cells, in part via the TLR4/NF-kB signaling pathway.

Quantitative iTRAQ-based proteomic analysis of rice grains to assess high night temperature stress.

Rice yield and quality are adversely affected by increasing global surface temperature, and are strongly attributed to high night temperature (HNT) than high daytime temperature. However, the molecular mechanism underlying the heat-tolerant characteristics of rice remains unclear. In the present study, we compared the proteomes of heat-tolerant and -sensitive lines of rice at early milky stage using an iTRAQ method. We have identified 38 differentially expressed proteins between the two lines, of which 32 proteins have been functionally annotated in NCBI and/or the UniProt database. These proteins were then classified into seven functional subgroups, which include signal transduction, transcript regulation, oxidation, defense response, transport, energy metabolism, and biosynthesis. Further analysis indicated that HNT stress could disrupt the redox equilibrium of plant cells, which in turn triggers the calcium-dependent protein kinase and COP9 signalosome, thereby regulating downstream genes/proteins that are involved in the HNT response. The candidate proteins may provide genetic resources for the improvement of heat-tolerant characteristics in rice, and the proposed model for signal transduction and transcriptional regulation may facilitate in the elucidation of the molecular mechanism underlying the response to HNT stress in rice.

Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

Communication: Molecular near-infrared transitions determined with sub-kHz accuracy.

Precise molecular transition frequencies are needed in various studies including the test of fundamental physics. Two well isolated ro-vibrational transitions of 12C16O at 1.57 µm, R(9) and R(10) in the second overtone band, were measured by a comb-locked cavity ring-down spectrometer. Despite the weakness of the lines (Einstein coefficient A≃0.008 s-1), Lamb-dip spectra were recorded with a signal-to-noise ratio over 1000, and the line positions were determined to be 191 360 212 761.1 and 191 440 612 662.2 kHz, respectively, with an uncertainty of 0.5 kHz (δν/ν=2.6×10-12). The present work demonstrates the possibility to explore extensive molecular lines in the near-infrared with sub-kHz accuracy.

Correlation between three glycometabolic-related hormones and muscle glycolysis, as well as meat quality, in three pig breeds.

BACKGROUND: The present study aimed to evaluate the correlations among muscle concentrations of three glycometabolic-related hormones (insulin, epinephrine and glucagon), muscle glycolysis and meat quality in representative muscles of either glycolytic or oxidative types. Moreover, the relative glycometabolic-related gene expression was measured. One Western crossbreed DLY (Duroc × (Landrace × Yorkshire)), one crossbreed with half-Chinese native-pig origin DL (Duroc × LiangShan) and one pure Chinese native pig TP (Tibetan pig) were used in the present study. RESULTS: Among the three breeds, DLY had the greatest glucagon and epinephrine (P < 0.01). Compared with DLY, TP and DL had lower lactic acid concentrations, showing lower glycolytic potentials (GP), greater ultimate pH values (P < 0.01) and lower relative expression levels of glycometabolic-related genes (GYS1, PRKAG3 and PKM2). Compared with the glycolytic muscle (musculus longissimus dorsi), oxidative muscle PM (musculus psoas major) had lower glucagon and epinephrine contents, lower GP and better meat quality. The concentration of glycometabolic-related hormones in the muscle had significant correlations with muscle glycolysis, meat pH and lightness. CONCLUSION: The results obtained in the present study imply that glucagon and epinephrine levels could be used to indicate early glycolytic metabolism during postmortem. These findings may be helpful in identifying pork with undesirable quality traits. 2016 Society of Chemical Industry.

Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases.

Metaplasticity is a higher form of synaptic plasticity that is essential for learning and memory, but its molecular mechanisms remain poorly understood. Here, we report that metaplasticity of transmission at CA1 synapses in the hippocampus is mediated by Src family kinase regulation of NMDA receptors (NMDARs). We found that stimulation of G-protein-coupled receptors (GPCRs) regulated the absolute contribution of GluN2A-versus GluN2B-containing NMDARs in CA1 neurons: pituitary adenylate cyclase activating peptide 1 receptors (PAC1Rs) selectively recruited Src kinase, phosphorylated GluN2ARs, and enhanced their functional contribution; dopamine 1 receptors (D1Rs) selectively stimulated Fyn kinase, phosphorylated GluN2BRs, and enhanced these currents. Surprisingly, PAC1R lowered the threshold for long-term potentiation while long-term depression was enhanced by D1R. We conclude that metaplasticity is gated by the activity of GPCRs, which selectively target subtypes of NMDARs via Src kinases.