The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics
Bibliographic record
Abstract
The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary. NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.
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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 | 0.001 |
| 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".