A heuristic model for working memory deficit in schizophrenia

• Type of Material: Article
• Authors: Zhen Qi, Georgia Institute of Technology; Gina P. Yu, Georgia Institute of Technology; Felix Tretter, Bertalanffy Center for the Study of Systems Science; Oliver Pogarell, University of Munich; Anthony A. Grace, University of Pittsburgh; Eberhard Voit, Emory University
• Language: English
• Date: 2016-11
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier B.V. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbagen.2016.04.031
• Title of Journal or Parent Work: Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids
• ISSN: 1388-1981
• Volume: 1860
• Issue: 11, Part B
• Start Page: 2696
• End Page: 2705
• Grant/Funding Information: This work was supported in part by grants from the National Institutes of Health (P01-ES016731, GWM, PI; R01HL095479) and an endowment from the Georgia Research Alliance (EOV, PI).
• Keywords: BASAL GANGLIA; NETWORK CONNECTIVITY; RAT-BRAIN; SUBTHALAMIC NUCLEUS ACTIVITY; Biochemistry & Molecular Biology; Mesoscopic model; GLUTAMATERGIC TRANSMISSION; Working memory deficit; VENTRAL TEGMENTAL AREA; PRIMATE PREFRONTAL CORTEX; IN-VIVO; Neurotransmitter; Science & Technology; INHIBITORY NEURONS; Biophysics; Systems biology; Schizophrenia; Interaction matrix; NEUROTRANSMITTER INTERACTIONS; Life Sciences & Biomedicine; Mobile
• Research Categories: Biology, Neuroscience; Engineering, Biomedical

Abstract

Background The life of schizophrenia patients is severely affected by deficits in working memory. In various brain regions, the reciprocal interactions between excitatory glutamatergic neurons and inhibitory GABAergic neurons are crucial. Other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine, modulate the local balance between glutamate and GABA and therefore regulate the function of brain regions. Persistent alterations in the balances between the neurotransmitters can result in working memory deficits. Methods Here we present a heuristic computational model that accounts for interactions among neurotransmitters across various brain regions. The model is based on the concept of a neurochemical interaction matrix at the biochemical level and combines this matrix with a mobile model representing physiological dynamic balances among neurotransmitter systems associated with working memory. Results The comparison of clinical and simulation results demonstrates that the model output is qualitatively very consistent with the available data. In addition, the model captured how perturbations migrated through different neurotransmitters and brain regions. Results showed that chronic administration of ketamine can cause a variety of imbalances, and application of an antagonist of the D 2 receptor in PFC can also induce imbalances but in a very different manner. Conclusions The heuristic computational model permits a variety of assessments of genetic, biochemical, and pharmacological perturbations and serves as an intuitive tool for explaining clinical and biological observations. General significance The heuristic model is more intuitive than biophysically detailed models. It can serve as an important tool for interdisciplinary communication and even for psychiatric education of patients and relatives.