Regulation of brain blood flow by astrocyte D-serine and N-methyl-D-aspartate receptors
Bibliographic record
Abstract
Functional hyperemia is an endogenous regulatory process coupling synaptic activity and elevated neuronal energy demand with increased local blood flow. This involves signalling between neurons, astrocytes and blood vessels, comprising the neurovascular unit. Astrocyte processes ensheath both synapses and blood vessels, permitting multi-modal responses to synaptic activity, where astrocyte cytoplasmic Ca2+ is elevated, triggering endfeet processes to release vasoactive molecules, such as arachidonic acid (AA) metabolites and gliotransmitters, such as D-serine. D-Serine is a co-agonist of the glycine regulatory site at N-methyl-D-aspartate (NMDA)-type glutamate receptors, and NMDA receptors play a role in functional hyperemia in vivo. Thus, our aim was to examine the role of astrocyte D-serine in NMDA receptor-mediated vasodilation. Using isolated pressurized mouse middle cerebral arteries (MCAs), we determined that co-application of glutamate and D-serine induced dose-dependent dilation which was mediated by NMDA receptors and endothelial nitric oxide synthase (eNOS) in an endothelial-dependent mechanism. This is the first evidence of direct vascular effects of D-serine and glutamate and suggests a possible role for endothelial NMDA receptor activation. Several studies indicate vascular endothelial cells express NMDA receptor subunits. However, expression in mouse endothelial cells has not been well characterized, so we identified NR1 and NR2C/2D subunit expression in primary brain endothelial cultures by PCR and immunocytochemistry, and further confirmed endothelial NR2C/2D expression in situ by immunohistochemistry. To further investigate astrocyte D-serine release and NMDA receptor-mediated functional hyperemia within the neurovascular unit, we used an acute cortical brain slice model where stimulation of astrocyte cytoplasmic Ca2+ induced vasodilation of nearby arterioles. Pharmacologically, D-serine release and NMDA receptor activation were implicated in this vasodilation. Endothelial-derived nitric oxide was also determined to induce dilation by inhibiting the production of an AA metabolite, 20-hydroxyeicostetranoic acid (20-HETE), a vasoconstrictor. This suggests an interaction between astrocyte vasoactive molecules, nitric oxide and D-serine, which warrants further investigation. Overall, our results provide evidence of modulation of NMDA receptor-mediated neurovascular coupling by astrocytic D-serine.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".