title: A heuristic model for working memory deficit in schizophrenia.
abstract: 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.
  
  
  
  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.
  
  
  
  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 D2 receptor in PFC can also induce imbalances but in a very different manner.
  
  
  
  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.
  
  
  
  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. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332, USA; Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: zhen.qi@gatech.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332, USA.
authors.forename: Gina P
authors.initials: GP
authors.lastname: Yu
authors.affiliation: Bertalanffy Center for the Study of Systems Science, 1040 Vienna, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Tretter
authors.affiliation: Dept. of Psychiatry, University of Munich, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pogarell
authors.affiliation: Department of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, 456 Langley Hall, Pittsburgh, PA, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Grace
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332, USA; Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Eberhard O
authors.initials: EO
authors.lastname: Voit
mesh_terms: D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003198:Computer Simulation; D018698:Glutamic Acid / Q000378:metabolism; D000066506:Heuristics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage; D008569:Memory Disorders; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D012559:Schizophrenia / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine
keywords: Interaction matrix; Mesoscopic model; Mobile; Neurotransmitter; Schizophrenia; Systems biology; Working memory deficit