N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca²⁺ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b. Both grin1a^–/– and grin1b^–/– zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a^–/–; grin1b^–/–), which lack all NMDAR-mediated synaptic transmission, survive until ~10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.

SIGNIFICANCE STATEMENT Rapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

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When thinking of this fruit we love so much what is the image that first pops to mind? Perhaps a green or a yellow with a greenish tint energy food? Or maybe a banana packaged in a perfect shade of yellow? If that’s the case, then it is time to broaden that perspective. Say hello to the Fe’i banana! This traditional [...]

"We thought it was a good idea to get a comprehensive record of the site while we could in case the water levels rise," says one official

We’re really, really sorry

Currently in the works, the new monument will honor her contributions and legacy with a contemplative space

Remote Isle au Haut is integrating time-tested technology with emerging innovations to create its own microgrid

A Guanaco (Lama guanicoe) surveys its surroundings from a vantage point at sunset, with the imposing Torres del Paine (Chile) in the background. Scouts like this individual keep an eye out for predators.

Residents can now order up to two bottles of wine, 24 cans of beer or more than a litre of spirits from local restaurants and bars.

Some farmers across the province are worried about getting their fuel in time for spring seeding. The Agricultural Producers Association of Saskatchewan says it has been fielding complaints this week about delays at the Co-op cardlock near Moose Jaw.

The Northwoods League announced Thursday that its 2020 season will not begin on May 26, as originally scheduled, due to the COVID-19 pandemic.

Parents-to-be who will have their new child delivered at the Thunder Bay Regional Health Sciences Centre have to follow a different set of guidelines than found at many other hospitals across Ontario.

<span class="topsy_trackback_comment"><span class="topsy_twitter_username"><span class="topsy_trackback_content">"Commonwealth Games will deliver" – ESPN STAR Sports | RSS Feeds ...: Globe and Mail"Commonwealth Games will deliv... http://bit.ly/9hmE8P</span></span>

<span class="topsy_trackback_comment"><span class="topsy_twitter_username"><span class="topsy_trackback_content">Squeekville, model train amusement park, on display at Children's ...: Squeekville, model train amusement park, ... http://bit.ly/9x4oFS</span></span>

The provincially appointed trustee of the English Montreal School Board says the Quebec government made the “right decision” when it postponed the reopening of Montreal-area elementary schools to May 25.

The soil is ready to be tilled and seeds wait to be planted at community gardens across Ottawa after the province reversed a decision declaring them off limits during the COVID-19 pandemic.

Canadian figure skater Scott Moir posted a video on Instagram and Twitter on Thursday, explaining that he and fiancee Jackie Mascarin are currently stationed in Tampa, Fla., because Mascarin works as a physician's assistant in the respiratory unit of a local hospital.

A fine and delicate balance in contemporary jazz  Telegraph India

Major League Soccer is easing its training restrictions, allowing clubs to use their practice fields but only for individual workouts and under strict rules.

The Vancouver Whitecaps said it has ordered two player to self-quarantine for 14 days after they violated club and league orders to abide by physical distancing guidelines in B.C.

Taking mom out for Mother's Day brunch is a tradition for many. But with people staying home and restaurants closed except for delivery or pick-up, this year's Mother's Day will be a little bit different. Food columnist Andrew Coppolino looks at options.

Matteo Tranchellini and Moreno Monti created a coffee table book called CHICken to showcase the natural beauty of the ubiquitous birds.

Karla Bell was outside an Orangeville hospital waiting to start her nursing shift when she heard a cry for help from a car in the parking lot. She ran up to find a woman in labour in the passenger seat. Natalie Kalata tells us the incredible story of how this baby was born.

An Essex County OPP officer has been slapped with a cut in pay because of "inexplicable" investigative delays into a fatal collision, allowing the at-fault driver to "evade criminal prosecution."

Documents created by the top disease investigators in the U.S. meant to give step-by-step advice to local leaders deciding when and how to reopen public places such as mass transit, day care centres and restaurants during the still-raging pandemic have been shelved by the Trump administration.

As British Columbians maintain physical distancing recommendations during the COVID-19 pandemic, this year’s Easter celebrations will have to change. In Kamloops, B.C., organizations are working to make sure Easter is as fun and social as it can be. 

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Bank of England Working Papers by Aydan Dogan and Ida Hjortsoe

European Systemic Risk Board Occasional Papers by Greg Ros

AppleInsider has rounded up the best 16-inch MacBook Pro deals going on right now, with coupon savings knocking up to $450 off every single model. Whether you're in the market for a standard config or looking for a loaded Core i9 model, it pays to check out the cash discounts.

Every year SOLIDWORKS hosts one of the largest engineering conferences in the world. Since SOLIDWORKS World 2000, Model Mania® has been an attraction for many engineers wanting to show off their SOLIDWORKS skills. Model Mania, for those not familiar, is a

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It’s always interesting to know about some cool tricks that you can use when it comes to modelling within SOLIDWORKS. Well, within this blog we just happen to have one of those tricks for you. They always say a magician never

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Learn how to easily delete a face from a solid or surface body when modeling in SOLIDWORKS. Our #TechTip this week is by Training Manager John Setzer. Video Transcript Hi and welcome to another GSC tech tip. Today we’re going

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Pursuant to Clearing Advisory 20-152 that was published on April 8th, the clearing house will switch the options pricing and valuation model to Bachelier to accommodate negative prices in the underlying futures and allow for listing of option contracts with negative strikes for the set of products specified in the link below. The switch will be effective for the margin cycle run at the end of trading tomorrow April 22, 2020 and will remain in place until further notice.

Click here for the full text of the advisory

20-170

One major goal of integrative and comparative biology is to understand and explain the interaction between the performance and behavior of animals in their natural environment. The Caviomorph, Octodon degu, is a native rodent species from Chile, and represents a unique model to study physiological and behavioral traits, including cognitive and sensory abilities. Degus live in colonies and have a well-structured social organization, with a mostly diurnal–crepuscular circadian activity pattern. More notable is the fact that in captivity, they reproduce and live between 5 and 7 yr and show hallmarks of neurodegenerative diseases (including Alzheimer's disease), diabetes, and cancer.

It’s been a nerve-wracking few years for the traditional auto industry. One Silicon Valley VC firm speculates on its future in an interview with Bloomberg.

OM EAST and a local partner prepare to send copies of the Right Choices Bible to the Nenets tribe on the Yamal Peninsula.

THE Murray window is closing but Tennis Scotland appear to be diving through it just in time. Failing to adequately capitalise on the ongoing successes of Andy and Jamie has been a long-time frustration of the family, with mum Judy vehement in her criticism of the governing bodies for their inertia.

Dandelion Cafe

Baker’s Delight

MY mother was known for her pizza but they were never round, not when we were growing up anyway. She would pull them from the ancient coal-fired cast iron range in the living room on long blackened oblong trays, the dough she had spent the day making puffed and undulating but always thin and super chewy.

Calabash African Restaurant

Sunday, April 19, 2020.

During the present crisis, many more of us are turning to Grow Your Own. This lets us enjoy much fresher and tastier veg than from a weekly shop, especially if that languishes in the fridge for days. And we won’t be relying on imports that could become less accessible.

A SCOTTISH clean energy company has secured a key part in a six-figure contract for a hydrogen fuel project in Northern Ireland.

Zinfandel Gastro Bar