LITHIUM OROTATE SELECTIVELY INHIBITS GSK3β WITHOUT IMPACT ON INOSITOL SIGNALLING
Bibliographic record
Abstract
Lithium Carbonate (LiCO) has been the standard pharmacological treatment for bipolar disorder (BD) for over half a century because it successfully reduces the manic and depressive \ncharacteristics of BD. Unfortunately, patients often discontinue LiCO treatment due to adverse physiological and cognitive side effects. LiCO treatment is limited by the narrow therapeutic \nwindow where high doses lead to toxicity or increased risk of side effects while lower doses are \nconsidered ineffective. Lithium orotate (LiOr) is an alternative treatment suggested to possess \nsuperior uptake properties compared to LiCO, which may reduce dosing requirements and lessen \ncognitive side effects. As LiOr yields higher brain lithium (Li+\n) than LiCO due to different \ntransport mechanisms and is only liberated intracellularly distant from the cell membrane, we \nhypothesize that 1) LiOr will be more potent than LiCl and 2) LiOr will selectively inhibit GSK3β \nto facilitate long-term potentiation (LTP) while LiCl acts closer to the membrane on N-methyl-D aspartate (NMDA) receptors and the phosphatidylinositol cycle. Dose-dependent LiCl and LiOr effects on synaptic plasticity were assessed in the hippocampal Schaffer collateral-CA1 synapse in male C57BL/6 mouse slices. LTP was induced by theta burst stimulations (TBS) (8 bursts at 5 Hz of 4 high-frequency pulses at 100 Hz repeated three times, 60 seconds apart) at 32℃. Long-term depression (LTD) was induced using a low frequency stimulation (LFS; 1 Hz) for 15 minutes at room temperature. We used typical therapeutic Li+ concentrations between 0.2-1.0 mM to assess Li+ effects on synaptic plasticity. We compared the effects the phosphoinositol cycle had on Li+\n-mediated effects on LTP by incubating \nslices in myo-inositol for 2-3 hours. We used basic pharmacology to determine the effects LiCl \nand LiOr had on GSK3β and NMDA receptors with 3.5 µM AZD2858, a non-specific GSK3Β \ninhibitor, and 5 µM DNQX to isolate NMDA currents. We found that LiCl and LiOr differentially affect synaptic plasticity by mediating different \nsecondary messenger pathways. All concentrations of LiOr influenced synaptic plasticity, but only \nhigher concentrations of LiCl altered LTP and LTD. We determined that LiCl had a dose dependent effect on the phosphatidylinositol pathway and NMDA receptors, whereas LiOr \nconsistently increased LTP through inhibition of GSK3β. Therapeutic LiCl concentrations demonstrate a dose-dependent response on synaptic \nplasticity, whereas LiOr has a consistent effect at both high and low concentrations. This differential effect could explain the contrasting findings on the effects LiCO has on cognition, as slight changes in Li+ concentration drastically change the synaptic response. This provides clinical \nrelevancy to BD research as it indicates LiOr is a more beneficial treatment for BD because it can \nbe prescribed at a lower dose than LiCO with the same effect. This study could influence clinical \nLi+ application and may lessen the adverse physiological and cognitive impact associated with Li+\ntreatment.
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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) | 0.003 | 0.001 |
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".