title: Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity.
abstract: OBJECTIVE
  Previous studies have suggested that the pathogenesis of schizophrenia and major depression involves an altered peripheral immune system. It is not clear, however, whether such changes are associated with corresponding neuroinflammatory responses and disturbances of neurotransmission.
  
  
  METHODS
  This paper reviews the current state of knowledge about the involvement of immune alterations in schizophrenia and major depression and a possible link to disturbances of glutamatergic transmission.
  
  
  RESULTS
  Inflammatory endogenous modulators of the NMDA receptor, the kynurenine pathway metabolites, are potential candidates for such a link. Studies of the blood and cerebrospinal fluid have suggested a schizophrenia-related upregulation of the NMDA receptor antagonist kynurenic acid in astrocytes, analogous to the ketamine psychosis model. Conversely, it has been proposed that there is depression-related microglial synthesis of the NMDA receptor agonist quinolinic acid, which is consistent with the observation that ketamine has therapeutic effects in major depression. Few publications have studied NMDA receptor modulating kynurenines in the brain, however.
  
  
  CONCLUSIONS
  Future research on the cerebral cell-type specific distribution of kynurenine metabolites and their brain-regional concentration imbalances will be required to connect peripheral immune changes, the hypotheses of blood-brain barrier dysfunction and glial pathology with concepts of altered neurotransmission in schizophrenia and major depression.
authors.affiliation: Department of Psychiatry, University of Magdeburg, Magdeburg, Germany. johann.steiner@med.ovgu.de
authors.forename: Johann
authors.initials: J
authors.lastname: Steiner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bogerts
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Sarnyai
authors.forename: Martin
authors.initials: M
authors.lastname: Walter
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gos
authors.forename: Hans-Gert
authors.initials: HG
authors.lastname: Bernstein
authors.forename: Aye-Mu
authors.initials: AM
authors.lastname: Myint
mesh_terms: D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D003865:Major Depressive Disorder / Q000276:immunology* / Q000378:metabolism*; D018698:Glutamic Acid / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology / Q000378:metabolism*; D012559:Schizophrenia / Q000276:immunology* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000276:immunology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D018698:Glutamic Acid