176.1 Bioenergetic Uncoupling of Astrocytes and Neurons May Underlie Cognitive Deficits in Schizophrenia
Bibliographic record
Abstract
Background: Pharmacologic, genetic, and theoretical considerations have firmly established schizophrenia as a disorder of excitatory synapses. Converging evidence from human schizophrenia studies and animal models of “broken” synapses suggest developing a brain with defective glutamatergic synapses yields metabolic abnormalities. This may be due to failure of astrocytes to develop/maintain metabolic coupling with glutamatergic neurons. Neurotransmission relies heavily on this metabolic coupling. For example, glycogen-rich glial cells synthesize pyruvate from glucose, convert pyruvate to lactate via lactate dehydrogenase (LDH), and transport lactate via monocarboxylate transporters (MCTs) to neurons for energetic use (the “lactate shuttle”). Working memory performance and long-term potentiation in rodents is impaired following disruption of MCTs. These findings suggest that bioenergetic coupling via the lactate shuttle is tightly coupled to cognitive function; thus, we hypothesized that these pathways are important pathophysiological substrates in chronic schizophrenia. Methods: To test this hypothesis, we assessed the integrity of the lactate shuttle and related metabolic pathways by adapting commercially available assays for use with postmortem brain. Results: We found significant decreases in LDH (~10%, P = .0484) and hexokinase (HXK; 24%, P = .0024) enzyme activity in the dorsolateral prefrontal cortex in schizophrenia. LDH and HXK activity were unchanged in the frontal cortex of haloperidol treated rats. There were no region-level changes in LDH, LDHA, LDHB, HXK, or MCT1 protein levels in schizophrenia. However, at the cell level, we found increases in MCT1 mRNA expression in both astrocytes and neurons. We have also assessed expression of metabolic substrates in an animal model of schizophrenia, the NR1 knockdown mouse. In this model of “broken” excitatory synapses, we found a 63% decrease in astrocytic MCT4 and 60% decrease in neuronal GLUT3 transcripts in NR1 KD mice versus wildtype. Conclusion: Our data suggest that LDH and HXK enzyme activity, and not expression, is decreased in schizophrenia, diminishing the ability of astrocytes to supply neurons with energetic substrates, which may impact cognition. Our animal studies support this hypothesis and suggest that alterations in the lactate shuttle and related pathways and metabolites in schizophrenia may be high-yield substrates to target for future drug development or imaging-based biomarkers. This work was supported by the NIMH (MH09445).
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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".