LITHIUM OROTATE SELECTIVELY INHIBITS GSK3β WITHOUT IMPACT ON INOSITOL SIGNALLING
| dc.contributor.advisor | Bekar, Lane K | |
| dc.contributor.committeeMember | Campanucci, Veronia A | |
| dc.contributor.committeeMember | Sawicki , Grzegorz | |
| dc.contributor.committeeMember | Botterill, Justin J | |
| dc.creator | Wark, Hannah Emily | |
| dc.creator.orcid | 0009-0009-6272-2870 | |
| dc.date.accessioned | 2023-10-03T19:32:24Z | |
| dc.date.available | 2023-10-03T19:32:24Z | |
| dc.date.copyright | 2023 | |
| dc.date.created | 2023-11 | |
| dc.date.issued | 2023-10-03 | |
| dc.date.submitted | November 2023 | |
| dc.date.updated | 2023-10-03T19:32:24Z | |
| dc.description.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 characteristics of BD. Unfortunately, patients often discontinue LiCO treatment due to adverse physiological and cognitive side effects. LiCO treatment is limited by the narrow therapeutic window where high doses lead to toxicity or increased risk of side effects while lower doses are considered ineffective. Lithium orotate (LiOr) is an alternative treatment suggested to possess superior uptake properties compared to LiCO, which may reduce dosing requirements and lessen cognitive side effects. As LiOr yields higher brain lithium (Li+ ) than LiCO due to different transport mechanisms and is only liberated intracellularly distant from the cell membrane, we hypothesize that 1) LiOr will be more potent than LiCl and 2) LiOr will selectively inhibit GSK3β to 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+ -mediated effects on LTP by incubating slices in myo-inositol for 2-3 hours. We used basic pharmacology to determine the effects LiCl and LiOr had on GSK3β and NMDA receptors with 3.5 µM AZD2858, a non-specific GSK3Β inhibitor, and 5 µM DNQX to isolate NMDA currents. We found that LiCl and LiOr differentially affect synaptic plasticity by mediating different secondary messenger pathways. All concentrations of LiOr influenced synaptic plasticity, but only higher 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 consistently increased LTP through inhibition of GSK3β. Therapeutic LiCl concentrations demonstrate a dose-dependent response on synaptic plasticity, 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 relevancy to BD research as it indicates LiOr is a more beneficial treatment for BD because it can be prescribed at a lower dose than LiCO with the same effect. This study could influence clinical Li+ application and may lessen the adverse physiological and cognitive impact associated with Li+ treatment. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/10388/15099 | |
| dc.language.iso | en | |
| dc.subject | Lithium Orotate | |
| dc.subject | Synaptic Plasticity | |
| dc.subject | Bipolar Disorder | |
| dc.title | LITHIUM OROTATE SELECTIVELY INHIBITS GSK3β WITHOUT IMPACT ON INOSITOL SIGNALLING | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Medicine | |
| thesis.degree.discipline | Anatomy, Physiology, and Pharmacology | |
| thesis.degree.grantor | University of Saskatchewan | |
| thesis.degree.level | Masters | |
| thesis.degree.name | Master of Science (M.Sc.) |