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NMDA Receptor Dysfunction and the Pathophysiology of Schizophrenia
Coyle Joseph
Harvard Medical School, USA
Dopamine has dominated the thinking about the pathophysiology of schizophrenia（SCZ）for nearly 50 years. Yet, dopamine D2 receptor blocking antipsychotic drugs have little effect on cognitive deficits and negative symptoms that are associated with poor out-come. Recent results from genome wide association studies and from the sequencing of copy number variants associated with SCZ have implicated genes encoding proteins involved in glutamatergic neurotransmission as risk genes for SCZ. This includes serine racemase（SR）, the enzyme responsible for the synthesis of D-serine, the co-agonist at NMDA receptors（R）, which is concentrated in the cortico-limbic regions. Mice homozygous for a SR null mutation（SR-/-）have less than 15% of wild-type（WT）levels of D-serine and have hypofuncytional NMDAR in the cortex and hippocampus. SR-/- mice exhibit many of the pathologic stigmata of SCZ including impaired working memory, increased ventricular volume, decreased cortical and hippocampal volume, reduced BDNF, phospho-TrkB, phospho-mTOR and reduced dendritic complexity and dendritic spines on cortical pyramidal neurons. Three-week treatment of SR-/- with doses of D-serine that normalizes its hippocampal levels reverses many of these deficits including BDNF levels and the activation of its down-stream mediators, LTP and cognitive impairments. Prior clinical trials in SCZ patients stabilized on antipsychotic drugs with agents that act at the glycine modulatory site on the NMDAR including D-serine and glycine have shown significant reductions in negative and cognitive symptoms and further reduction in positive symptoms.
To understand better the localization of SR and D-serine, we used a combination of quantitative genetic and immunologic methods. SR expression was blocked in a cell specific fashion using mice expressing Cre in astrocytes with a GFAP promoter and in forebrain glutamatergic neurons with CAMKIIα promoter. Cortical D-serine levels were unaffected in the astrocyte SR knock-out（KO）and were reduced by only 30% in the glutamatergic SRKO. We found that neither SR nor D-serine was expressed in the astrocytes in the adult brain, but virtually all SR and D-serine were localized to neurons in neocortex. Over half of the D-serine positive neurons were GABAergic interneurons with the majority of these expressing somatostatin and/or parvalbumin（PV）. These findings are consistent with D-serine serving as the co-transmitter with glutamate in cortico-limbic glutamatergic neurons and raise questions about the role of D-serine localized to cortical PV+GABAergic interneurons, which are down regulated in SCZ. Thus, NMDAR dysregulation appears to be a critical feature of SCZ and a target for future drug development.
JT Coyle, MD has consulted with AbbVie and EnVivo within the last 2 years and holds a patent on the clinical use of D-serine that is owned by Massachusetts General Hospital. This research was supported by grants from the N.I.H. | | | |
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