Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

AbstractIn the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in juvenile hippocampal slices but the involvement of particular NMDAR subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus. A concentration of Ro (1 μM) that selectively blocks GluN2B-containing diheteromers is able to block LTD. It also inhibits a component of STP without affecting LTP. A higher concentration of Ro (10 μM), that also inhibits GluN2A/B triheteromers, blocks LTP. UBP145 selectively inhibits the Ro-sensitive component of STP whereas NVP inhibits LTP. These data are consistent with a role of GluN2B diheretomers in LTD, a role of both GluN2B- and GluN2D- containing NMDARs in STP and a role of GluN2A/B triheteromers in LTP.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’

Aggressive treatment of metastatic squamous cell carcinoma of the rectum to the liver: a case report and a brief review of the literature

BACKGROUND: Rectal squamous cell carcinoma (SCC) is a rare tumor. The incidence of this malignancy has been reported to be 0.25 to 1 per 1000 colorectal carcinomas. From a review of the English literature 55 cases of SCC of the rectum have been published. In this study we report a rectal metastatic SCC to the liver, discussing the efficacy of aggressive adjuvant and neo-adjuvant therapies on survival and prognosis. CASE PRESENTATION: A 39-year-old female patient with a pure SCC of the rectum diagnosed endoscopically is presented. The patient underwent initially neoadjuvant chemo-radiotherapy and then abdominoperineal resection with concomitant bilateral oophorectomy and hysterectomy, followed by adjuvant chemo-radiotherapy. Five months after the initial operation liver metastasis was demonstrated and a liver resection was carried out, followed by adjuvant chemotherapy. Eighteen months after the initial operation the patient is alive. CONCLUSION: Although prognosis of rectal SCC is worse than that of adenocarcinoma, an aggressive therapeutic approach with surgery as the primary treatment, followed by combined neo- and adjuvant chemo-radiotherapy, may be necessary in order to improve survival and prognosis

Methodological limitations of psychosocial interventions in patients with an implantable cardioverter-defibrillator (ICD) A systematic review

<p>Abstract</p> <p>Background</p> <p>Despite the potentially life-saving benefits of the implantable cardioverter-defibrillator (ICD), a significant group of patients experiences emotional distress after ICD implantation. Different psychosocial interventions have been employed to improve this condition, but previous reviews have suggested that methodological issues may limit the validity of such interventions. Aim: To review the methodology of previously published studies of psychosocial interventions in ICD patients, according to CONSORT statement guidelines for non-pharmacological interventions, and provide recommendations for future research.</p> <p>Methods</p> <p>We electronically searched the PubMed, PsycInfo and Cochrane databases. To be included, studies needed to be published in a peer-reviewed journal between 1980 and 2008, to involve a human population aged 18+ years and to have an experimental design.</p> <p>Results</p> <p>Twelve studies met the eligibility criteria. Samples were generally small. Interventions were very heterogeneous; most studies used cognitive behavioural therapy (CBT) and exercise programs either as unique interventions or as part of a multi-component program. Overall, studies showed a favourable effect on anxiety (6/9) and depression (4/8). CBT appeared to be the most effective intervention. There was no effect on the number of shocks and arrhythmic events, probably because studies were not powered to detect such an effect. Physical functioning improved in the three studies evaluating this outcome. Lack of information about the indication for ICD implantation (primary vs. secondary prevention), limited or no information regarding use of anti-arrhythmic (9/12) and psychotropic (10/12) treatment, lack of assessments of providers' treatment fidelity (12/12) and patients' adherence to the intervention (11/12) were the most common methodological limitations.</p> <p>Conclusions</p> <p>Overall, this review supports preliminary evidence of a positive effect of psychosocial interventions on anxiety and physical functioning in ICD patients. However, these initial findings must be interpreted cautiously because of important methodological limitations. Future studies should be designed as large RCTs, whose design takes into account the specific challenges associated with the evaluation of behavioural interventions.</p

Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist

In a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30?min and 24?h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.Acknowledgements: M.G.-S. was recipient of a contract from the Sistema Nacional de Garantía Juvenil co-funded by the European Social Fund. We also thank Novartis for the generous gift of NVP-AAM077. This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13/00038 and PI16/00217) that were co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation

N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes

Changing outcomes following pelvic exenteration for locally advanced and recurrent rectal cancer

Background Pelvic exenteration for locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) is technically challenging but increasingly performed in specialist centres. The aim of this study was to compare outcomes of exenteration over time. Methods This was a multicentre retrospective study of patients who underwent exenteration for LARC and LRRC between 2004 and 2015. Surgical outcomes, including rate of bone resection, flap reconstruction, margin status and transfusion rates, were examined. Outcomes between higher- and lower-volume centres were also evaluated. Results Some 2472 patients underwent pelvic exenteration for LARC and LRRC across 26 institutions. For LARC, rates of bone resection or flap reconstruction increased from 2004 to 2015, from 3.5 to 12.8 per cent, and from 12.0 to 29.4 per cent respectively. Fewer units of intraoperative blood were transfused over this interval (median 4 to 2 units; P = 0.040). Subgroup analysis showed that bone resection and flap reconstruction rates increased in lower- and higher-volume centres. R0 resection rates significantly increased in low-volume centres but not in high-volume centres over time (low-volume: from 62.5 to 80.0 per cent, P = 0.001; high-volume: from 83.5 to 88.4 per cent, P = 0.660). For LRRC, no significant trends over time were observed for bone resection or flap reconstruction rates. The median number of units of intraoperative blood transfused decreased from 5 to 2.5 units (P < 0.001). R0 resection rates did not increase in either low-volume (from 51.7 to 60.4 per cent; P = 0.610) or higher-volume (from 48.6 to 65.5 per cent; P = 0.100) centres. No significant differences in length of hospital stay, 30-day complication, reintervention or mortality rates were observed over time. Conclusion Radical resection, bone resection and flap reconstruction rates were performed more frequently over time, while transfusion requirements decreased

Probing spatial and subunit-dependent signalling by the NMDA receptor

NMDARs are ligand-gated cation channels which are activated by the neurotransmitter glutamate. NMDARs are essential in coupling electrical activity to biochemical signalling as a consequence of their high Ca2+ permeability. This Ca2+ influx acts as a secondary messenger to mediate neurodevelopment, synaptic plasticity, neuroprotection and neurodegeneration. The biological outcome of NMDAR activation is determined by a complicated interrelationship between the concentration of Ca2+ influx, NMDAR location (synaptic vs. extrasynaptic) as well as the subtype of the GluN2 subunit. Despite the recognition that NMDAR mediated physiology is multifaceted, tools used to study subunit and location dependent signalling are poorly characterized and in other cases, non-existent. Therefore, the aim of this thesis is to address this issue. Firstly, I assessed the current pharmacological approach used to selectively activate extrasynaptic NMDARs. Here, synaptic NMDARs are first blocked with MK-801 during phasic activation and then extrasynaptic NMDARs are tonically activated. This approach relies on the continual irreversible blockade of synaptic NMDARs by MK-801 yet contrary to the current dogma, I demonstrate this blockade is unstable during tonic agonist exposure and even more so when physiologically relevant concentrations of Mg2+ are present. This confines a temporal limit in which selective activation of extrasynaptic NMDARs can occur with significant consequences for studying synaptic vs. extrasynaptic NMDAR signalling. Dissecting subunit-dependent signalling mediated by the two major GluN2 subunits in the forebrain, GluN2A and GluN2B, has been advanced significantly by selective GluN2B antagonism yet a reciprocal GluN2A selective antagonist has been lacking. Utilizing novel GluN2A-specific antagonists, I demonstrate a developmental upregulation of GluN2A-mediated NMDA currents which concurrently dilutes the contribution of GluN2B-mediated currents. Moreover, I tested the hypothesis that the Cterminus of GluN2A and GluN2B are essential in controlling the developmental switch of GluN2 subunits utilizing knock-in mice whereby the C-terminus of GluN2A is replaced with that of GluN2B. Surprisingly, the exchange of the C-terminus does not impede the developmental switch in subunits nor the proportion of NMDARs at synaptic vs extrasynaptic sites. However, replacing the C-terminus of GluN2A with that of GluN2B induces a greater neuronal vulnerability to NMDA-dependent excitotoxicity. Collectively, this work enhances our understanding of the complex physiology mediated by the NMDAR by determining how pharmacological tools are best utilized to study the roles of NMDAR location and subunit composition in addition to revealing the importance of the GluN2 C-terminus in development and excitotoxicity