Reduced Microglial Activity and Enhanced Glutamate Transmission in the Basolateral Amygdala in Early CNS Autoimmunity
Bibliographic record
Abstract
Emotional dysfunction is common in multiple sclerosis (MS) patients and in mouse models of MS, including experimental autoimmune encephalomyelitis (EAE); however, the etiology of these behaviors is poorly understood. To identify CNS changes associated with these behaviors, we focused on the basolateral amygdala (BLA) because of its central role in the regulation of emotional behavior. Whole-cell recordings were performed in the principal neurons of the BLA in early EAE, before demyelination, T-cell invasion, and motor dysfunction. EAE female mice displayed increased frequency of mEPSCs, with no alteration in amplitude or evoked EPSC paired-pulse ratio compared with controls. We found an increase in the AMPA-NMDA ratio and dendritic spine density, indicating increased numbers of glutamatergic synapses. We saw similar electrophysiological changes in BLA principal neurons after microglia were either inactivated (minocycline) or depleted (Mac1-Saporin) in the BLA. Microglia regulate synapses through pruning, directed by complement protein 3 (C3) expression. C3 was downregulated in the BLA in EAE. Ultrastructural analysis of microglia revealed more complex ramifications and reduced extracellular digestion of cellular elements. We also observed reduced IBA-1 and CD68 staining and lack of proinflammatory cytokine expression in the amygdala. Thus, early EAE is a state of microglial “deactivation” associated with reduced synaptic pruning. This contrasts with the prototypic microglial activation commonly associated with inflammatory CNS disease. Additionally, these data support a role for the acquired immune system to influence both neuronal and microglial function in early CNS autoimmunity. SIGNIFICANCE STATEMENTMicroglia help regulate synaptic homeostasis, but there has been little evidence for how this might be important in neuroinflammatory diseases. The data from this study reveal increased synaptic activity and spine density in early stages of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) in the basolateral amygdala, a nucleus important in the types of behavioral changes we have previously described. These electrophysiological and morphological effects occurred without significant elevation of local inflammatory cytokines or local demyelination. Unexpectedly, in the context of inflammatory state, we found that microglia were “deactivated.” This study provides strong evidence for a link between microglial activity and synaptic function; the conclusions contrast with the generally accepted view that microglia are activated in inflammatory disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".