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

Investigating Factors That Influence Food Cue Reactivity in Humans

The 21st century rise in obesity coincides with the increased prevalence of palatable, energy-dense foods and the ubiquitous cues signaling their availability. Food cue reactivity refers to the responses to these cues – such as increased salivation, brain activity, or the cognitive experience of craving – that become conditioned through prior consumption. Food cue reactivity is highly predictive of food intake and body weight; however, the mechanisms underlying risk are poorly understood. The overarching goal of this dissertation is to investigate factors that influence food cue reactivity in humans. Over three experiments, I examined factors related to the individual or to the food itself. First, it is well understood that gut-brain signals generated during nutrient digestion are the primary reinforcers behind the conditioning of environmental signals into food-predictive cues. I therefore tested the roles of both nutritional factors including energy density and macronutrient composition and individual factors such as food liking and perceived healthiness in the subjective valuation of food (Chapters 2 and 3). This work revealed that individuals with healthy weight, but not with obesity, find foods containing roughly equal amounts of fat and carbohydrate in combination more reinforcing than foods with predominantly fat or carbohydrate in isolation (Chapter 3). Second, given that prior work has implicated the olfactory system in obesity risk, I examined whether central olfactory coding impacts reactivity to food odors (Chapters 4 and 5). I showed that the ability to decode odor quality from distributed brain patterns captured with functional magnetic resonance imaging correlates with cue-potentiated feeding in the sated state (Chapter 4). Finally, mental imagery involves the reactivation of sensory circuits and is thought to intensify craving. Since previous research has shown that odor but not visual imagery ability varies widely across the population and positively correlates with body mass index, I investigated the specific contributions of odor imagery ability to food cue reactivity. Across multiple measures, I found that better odor imagery ability predicts larger changes in adiposity via elevated cue-induced craving and intake (Chapter 5). The studies in this dissertation collectively support a model by which humans are generally more cue reactive to foods rich in added fat and sugar, with olfactory coding and mental imagery influencing individual susceptibility for overeating and weight gain

The effects of scanning on the detection of targets.

http://www.archive.org/details/effectsofscannin00persU.S. Navy (U.S.N.) author

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

Fat and Carbohydrate Interact to Potentiate Food Reward in Healthy Weight but Not in Overweight or Obesity

Prior work suggests that actual, but not estimated, energy density drives the reinforcing value of food and that energy from fat and carbohydrate can interact to potentiate reward. Here we sought to replicate these findings in an American sample and to determine if the effects are influenced by body mass index (BMI). Thirty participants with healthy weight (HW; BMI 21.92 ± 1.77; M ± SD) and 30 participants with overweight/obesity (OW/OB; BMI 29.42 ± 4.44) rated pictures of common American snacks in 120-kcal portions for liking, familiarity, frequency of consumption, expected satiety, healthiness, energy content, energy density, and price. Participants then completed an auction task where they bid for the opportunity to consume each food. Snacks contained either primarily carbohydrate, primarily fat, or roughly equal portions of fat and carbohydrate (combo). Replicating prior work, we found that participants with HW bid the most for combo foods in linear mixed model analyses. This effect was not observed among individuals with OW/OB. Additionally, in contrast with previous reports, our linear regression analyses revealed a negative relationship between the actual energy density of the snacks and bid amount that was mediated by food price. Our findings support altered macronutrient reinforcement in obesity and highlight potential influences of the food environment on the regulation of food reward

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

Functional effects of disease-associated variants reveal that the S1-M1 linker of the NMDA receptor critically controls channel opening.

The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation

The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.Altérations du système de récompense dans l'anorexie mentaleRole du biostatus en acides gras polyinsaturés dans les troubles de contrôle exécuti