LITHIUM OROTATE SELECTIVELY INHIBITS GSK3β WITHOUT IMPACT ON INOSITOL SIGNALLING
Date
2023-10-03
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0009-0009-6272-2870
Type
Thesis
Degree Level
Masters
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.
Description
Keywords
Lithium Orotate, Synaptic Plasticity, Bipolar Disorder
Citation
Degree
Master of Science (M.Sc.)
Department
Medicine
Program
Anatomy, Physiology, and Pharmacology