Distinctive effects of NMDA receptor modulators on cerebral microcirculation in a schizophrenia mouse model
Jun Ju1, Luping Liu2, Xinyi Yang1
1Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, China.
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.
Insights
Schizophrenia reduces cerebral microcirculation. D-serine, targeting NMDA receptors (NMDARs), restored blood flow in a mouse model, suggesting NMDARs regulate microcirculation via inhibitory neuron activity.
Area of Science:
- Neuroscience
- Cerebrovascular Biology
- Neuropharmacology
Background:
- Schizophrenia is linked to altered cerebral microcirculation, but the specific changes in cerebral microcirculatory blood flow (microCBF) remain unclear.
- Understanding these microcirculatory changes is crucial for developing effective treatments for schizophrenia.
Purpose of the Study:
- To investigate the changes in microCBF in a mouse model of schizophrenia.
- To explore the role of N-methyl-D-aspartate receptors (NMDARs) in regulating microCBF reduction in schizophrenia.
Main Methods:
- Time-lapse two-photon imaging of individual capillaries was used to assess microCBF.
- Pharmacological agents, including D-serine and GNE-8324, were administered to modulate NMDAR function.
Main Results:
- A significant decrease in cerebral microcirculation was observed in the schizophrenia mouse model.
- D-serine administration markedly increased microCBF in schizophrenia mice.
- GNE-8324, a GluN2A-selective NMDAR modulator, did not affect microCBF in schizophrenia mice.
Conclusions:
- NMDARs play a role in regulating microcirculation in schizophrenia.
- This regulation appears dependent on tonic NMDAR signaling and selective modulation of inhibitory neuron activity.
- Further research is needed to fully elucidate the NMDAR-mediated mechanisms influencing microcirculation in schizophrenia.
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