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An Ensemble Approach to Predict Schizophrenia Using Protein Data in the N-methyl-D-Aspartate Receptor (NMDAR) and Tryptophan Catabolic Pathways.

ABSTRACT: In the wake of recent advances in artificial intelligence research, precision psychiatry using machine learning techniques represents a new paradigm. The D-amino acid oxidase (DAO) protein and its interaction partner, the D-amino acid oxidase activator (DAOA, also known as G72) protein, have been implicated as two key proteins in the N-methyl-D-aspartate receptor (NMDAR) pathway for schizophrenia. Another potential biomarker in regard to the etiology of schizophrenia is melatonin in the tryptophan catabolic pathway. To develop an ensemble boosting framework with random undersampling for determining disease status of schizophrenia, we established a prediction approach resulting from the analysis of genomic and demographic variables such as DAO levels, G72 levels, melatonin levels, age, and gender of 355 schizophrenia patients and 86 unrelated healthy individuals in the Taiwanese population. We compared our ensemble boosting framework with other state-of-the-art algorithms such as support vector machine, multilayer feedforward neural networks, logistic regression, random forests, naive Bayes, and C4.5 decision tree. The analysis revealed that the ensemble boosting model with random undersampling [area under the receiver operating characteristic curve (AUC) = 0.9242 ± 0.0652; sensitivity = 0.8580 ± 0.0770; specificity = 0.8594 ± 0.0760] performed maximally among predictive models to infer the complicated relationship between schizophrenia disease status and biomarkers. In addition, we identified a causal link between DAO and G72 protein levels in influencing schizophrenia disease status. The study indicates that the ensemble boosting framework with random undersampling may provide a suitable method to establish a tool for distinguishing schizophrenia patients from healthy controls using molecules in the NMDAR and tryptophan catabolic pathways.

SUBMITTER: Lin E

PROVIDER: S-EPMC7287032 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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An Ensemble Approach to Predict Schizophrenia Using Protein Data in the N-methyl-D-Aspartate Receptor (NMDAR) and Tryptophan Catabolic Pathways.

Lin Eugene E Lin Chieh-Hsin CH Hung Chung-Chieh CC Lane Hsien-Yuan HY

Frontiers in bioengineering and biotechnology 20200604

In the wake of recent advances in artificial intelligence research, precision psychiatry using machine learning techniques represents a new paradigm. The D-amino acid oxidase (DAO) protein and its interaction partner, the D-amino acid oxidase activator (DAOA, also known as G72) protein, have been implicated as two key proteins in the N-methyl-D-aspartate receptor (NMDAR) pathway for schizophrenia. Another potential biomarker in regard to the etiology of schizophrenia is melatonin in the tryptoph ...[more]

PMID: 32582679

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Project description:N-methyl-d-aspartate receptors (NMDARs) mediate both physiological and pathophysiological processes, although selective ligands lack broad clinical utility. NMDARs are composed of multiple subunits, but N-methyl-d-aspartate receptor subunit 2 (GluN2) is predominately responsible for functional heterogeneity. Specifically, the GluN2A- and GluN2B-containing subtypes are enriched in adult hippocampus and cortex and impact neuronal communication via dynamic trafficking into and out of the synapse. We sought to understand if ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl) butanamide (NYX-2925), a novel NMDAR modulator, alters synaptic levels of GluN2A- or GluN2B-containing NMDARs. Low-picomolar NYX-2925 increased GluN2B colocalization with the excitatory post-synaptic marker post-synaptic density protein 95 (PSD-95) in rat primary hippocampal neurons within 30 min. Twenty-four hours following oral administration, 1 mg/kg NYX-2925 increased GluN2B in PSD-95-associated complexes ex vivo, and low-picomolar NYX-2925 regulated numerous trafficking pathways in vitro. Because the NYX-2925 concentration that increases synaptic GluN2B was markedly below that which enhances long-term potentiation (mid-nanomolar), we sought to elucidate the basis of this effect. Although NMDAR-dependent, NYX-2925-mediated colocalization of GluN2B with PSD-95 occurred independent of ion flux, as colocalization increased in the presence of either the NMDAR channel blocker (5R,10S)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate or glycine site antagonist 7-chlorokynurenic acid. Moreover, while mid-nanomolar NYX-2925 concentrations, which do not increase synaptic GluN2B, enhanced calcium transients, functional plasticity was only enhanced by picomolar NYX-2925. Thus, NYX-2925 concentrations that increase synaptic GluN2B facilitated the chemical long-term potentiation induced insertion of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunit levels. Basal (unstimulated by chemical long-term potentiation) levels of synaptic GluA1 were only increased by mid-nanomolar NYX-2925. These data suggest that NYX-2925 facilitates homeostatic plasticity by initially increasing synaptic GluN2B via metabotropic-like NMDAR signaling. Cover Image for this issue: doi: 10.1111/jnc.14735.

Dataset Information

An Ensemble Approach to Predict Schizophrenia Using Protein Data in the N-methyl-D-Aspartate Receptor (NMDAR) and Tryptophan Catabolic Pathways.

Publications

An Ensemble Approach to Predict Schizophrenia Using Protein Data in the N-methyl-D-Aspartate Receptor (NMDAR) and Tryptophan Catabolic Pathways.

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