Distinctive effects of NMDA receptor modulators on cerebral microcirculation in a schizophrenia mouse model

Abstract

Substantial evidence demonstrates that schizophrenia patients have altered cerebral microcirculation. However, little is known regarding how cerebral microcirculatory blood flow (microCBF) changes in schizophrenia. Here, using time-lapse two-photon imaging of individual capillaries, we demonstrated a substantial decrease in cerebral microcirculation in a mouse model of schizophrenia. The involvement of NMDA receptor (NMDAR) functions was investigated to understand further the mechanism of microcirculation reduction in this animal model. Administration of D-serine, a selective full agonist at the glycine site of NMDAR, significantly increased the microCBF in the schizophrenia mouse. Interestingly, administration of GNE-8324, a GluN2A-selective positive allosteric modulator that selectively enhances NMDAR-mediated synaptic responses in inhibitory but not excitatory neurons, had no effect on the microCBF of the schizophrenia mice. Together, these data indicated that NMDAR participated in the regulation of microcirculation in schizophrenia using a mechanism dependent on the tonic NMDAR signaling and the selective modulation of inhibitory neuron activity. Further studies are warranted to establish NMDAR's role in modulating microcirculation in schizophrenia.