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.

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.