Structure, function, and allosteric modulation of NMDA receptors

NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca(2+)-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor

Identification of a brain fingerprint for overweight and obesity

The brain plays a central role in the pathophysiology of overweight and obesity. Connectome-based Predictive Modeling (CPM) is a newly developed, data-driven approach that exploits whole-brain functional connectivity to predict a behavior or trait that varies across individuals. We used CPM to determine whether brain “fingerprints” evoked during milkshake consumption could be isolated for common measures of adiposity in 67 adults with overweight and obesity. We found that CPM captures more variance in waist circumference than either percent body fat or BMI, the most frequently used measures to assess brain correlates of obesity. In a post-hoc analysis, we were also able to derive a largely separable functional connectivity network predicting fasting blood insulin. These findings suggest that, in individuals with overweight and obesity, brain network patterns may be more tightly coupled to waist circumference than BMI or percent body fat and that adiposity and glucose tolerance are associated with distinct maps, pointing to dissociable central pathophysiological phenotypes for obesity and diabetes.</p

Classification of Missense Variants in the N-Methyl-D-Aspartate Receptor GRIN Gene Family as Gain- Or Loss-of-Function

Advances in sequencing technology have generated a large amount of genetic data from patients with neurological conditions. These data have provided diagnosis of many rare diseases, including a number of pathogenic de novo missense variants in GRIN genes encoding N-methyl-d-aspartate receptors (NMDARs). To understand the ramifications for neurons and brain circuits affected by rare patient variants, functional analysis of the variant receptor is necessary in model systems. For NMDARs, this functional analysis needs to assess multiple properties in order to understand how variants could impact receptor function in neurons. One can then use these data to determine whether the overall actions will increase or decrease NMDAR-mediated charge transfer. Here, we describe an analytical and comprehensive framework by which to categorize GRIN variants as either gain-of-function (GoF) or loss-of-function (LoF) and apply this approach to GRIN2B variants identified in patients and the general population. This framework draws on results from six different assays that assess the impact of the variant on NMDAR sensitivity to agonists and endogenous modulators, trafficking to the plasma membrane, response time course and channel open probability. We propose to integrate data from multiple in vitro assays to arrive at a variant classification, and suggest threshold levels that guide confidence. The data supporting GoF and LoF determination are essential to assessing pathogenicity and patient stratification for clinical trials as personalized pharmacological and genetic agents that can enhance or reduce receptor function are advanced. This approach to functional variant classification can generalize to other disorders associated with missense variants

Beyond the Imitation Game: Quantifying and extrapolating the capabilities of language models

Language models demonstrate both quantitative improvement and new qualitative capabilities with increasing scale. Despite their potentially transformative impact, these new capabilities are as yet poorly characterized. In order to inform future research, prepare for disruptive new model capabilities, and ameliorate socially harmful effects, it is vital that we understand the present and near-future capabilities and limitations of language models. To address this challenge, we introduce the Beyond the Imitation Game benchmark (BIG- bench). BIG-bench currently consists of 204 tasks, contributed by 450 authors across 132 institutions. Task topics are diverse, drawing problems from linguistics, childhood develop- ment, math, common-sense reasoning, biology, physics, social bias, software development, and beyond. BIG-bench focuses on tasks that are believed to be beyond the capabilities of current language models. We evaluate the behavior of OpenAI's GPT models, Google- internal dense transformer architectures, and Switch-style sparse transformers on BIG-bench, across model sizes spanning millions to hundreds of billions of parameters. In addition, a team of human expert raters performed all tasks in order to provide a strong baseline. Findings include: model performance and calibration both improve with scale, but are poor in absolute terms (and when compared with rater performance); performance is remarkably similar across model classes, though with benefits from sparsity; tasks that improve gradually and predictably commonly involve a large knowledge or memorization component, whereas tasks that exhibit "breakthrough" behavior at a critical scale often involve multiple steps or components, or brittle metrics; social bias typically increases with scale in settings with ambiguous context, but this can be improved with prompting

Hodgkin-Huxley-Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

Glutamate receptors are essential ligand-gated ion channels in the central nervous system that mediate excitatory synaptic transmission in response to the release of glutamate from presynaptic terminals. The structural and biophysical basis underlying the function of these receptors has been studied for decades by a wide range of approaches. However recent structural, pharmacological and genetic studies have provided new insight into the regions of this protein that are critical determinants of receptor function. Lack of variation in specific areas of the protein amino acid sequences in the human population has defined three regions in each receptor subunit that are under selective pressure, which has focused research efforts and driven new hypotheses. In addition, these three closely positioned elements reside near a cavity that is shown by multiple studies to be a likely site of action for allosteric modulators, one of which is currently in use as an FDA-approved anticonvulsant. These structural elements are capable of controlling gating of the pore, and appear to permit some modulators bound within the cavity to also alter permeation properties. This creates a new precedent whereby features of the channel pore can be modulated by exogenous drugs that bind outside the pore. The convergence of structural, genetic, biophysical and pharmacological approaches is a powerful means to gain insight into the complex biological processes defined by neurotransmitter receptor function

Structural determinants of agonist efficacy at the glutamate binding site of n-methyl-d-Aspartate receptorss

N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1–72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits

No evidence for an association between obesity and food liking

Background: Prevailing models of obesity posit that hedonic signals override homeostatic mechanisms to promote overeating in today’s food environment. What researchers mean by “hedonic” varies considerably, but most frequently refers to an aggregate of appetitive events including incentive salience, motivation, reinforcement, and perceived pleasantness. Here we define hedonic as orosensory pleasure experienced during eating and set out to test whether there is a relationship between adiposity and the perceived pleasure of a palatable and very energy dense milkshake. Methods: The perceived liking, wanting and intensity of two palatable and energy-dense milkshakes were assessed using the labeled hedonic scale (1), visual analogue scale, and Generalized Labeled Magnitude Scale (2) in 110 individuals ranging in body mass index (BMI) from 19.3 to 52.1 kg/m2. Waist circumference, waist-hip ratio, and percent body fat were also measured. Importantly, unlike the majority of prior studies, we attempted to standardize internal state by instructing participants to arrive to the laboratory neither hungry nor full and at least one-hour fasted. Hunger ratings were also examined prior to hedonic measurement and included as covariates in our analyses. Results: Data were analyzed with general linear and linear mixed effects models (GLMs). We identified a significant association between ratings of hunger and milkshake liking and wanting. By contrast, we found no evidence for a relationship between any measure of adiposity and ratings of milkshake liking, wanting, or intensity. Conclusions: We conclude that adiposity is not associated with the pleasure experienced during consumption of our energy-dense and palatable milkshakes. Our results provide evidence against the hypothesis that heightened hedonic signals drive weight gain