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

Objectives. 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.

Key words::

• Major depression
• schizophrenia
• blood–brain barrier
• psychoimmunology
• kynurenines
• glutamate

Acknowledgments

This work was partially supported by grants of the Commission of European Communities 7th Framework Programme Collaborative Project MOODINFLAME to A.M.M. (Grant No. 22963) and of the Stanley Medical Research Foundation to BB and JS (Grant No. 07R-1832). Pembroke College (University of Cambridge, Cambridge, UK) has invited JS as a visiting scholar.

Statement of Interest

The authors declare no conflict of interest.