Synaptic Mechanisms Underlying Treatment of Depression and Bipolar Disorder




Gideons, Erinn Sommer

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Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that elicits rapid antidepressant responses in depressed patients. However, ketamine can also produce psychotomimetic effects, which limits its widespread use. The field has been exploring the mechanism of ketamine's antidepressant action to assist in identifying drugs that may also produce the rapid effects without the potential side effects. Memantine is a NMDAR antagonist similar to ketamine in many regards but does not produce antidepressant effects in patients. Behavioral experiments in mice recapitulated clinical findings showing that ketamine but not memantine has antidepressant-like effects in two common antidepressant efficacy tests. Ketamine and memantine effectively blocked NMDAR-mediated mEPSCs in the absence of Mg2+. However, in physiological levels of extracellular Mg2+ only ketamine was able to block the NMDAR at rest. This difference between ketamine and memantine extended to intracellular signaling coupled to NMDAR at rest, in that ketamine inhibits the phosphorylation of eukaryotic elongation factor 2 (eEF2) resulting in an augmentation of subsequent protein expression of brain-derived neurotrophic factor (BDNF), that is not triggered by memantine These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDA receptor mediated neurotransmission that impacts downstream intracellular signaling which is hypothesized as the trigger for rapid antidepressant responses. In a subsequent study, the therapeutic effect of lithium, a mood stabilizer and a common treatment for Bipolar Disorder (BD) is being investigated. Lithium has antidepressant and antimanic effects in patients with BD that can be recapitulated in animal models. While lithium is effective as a mood stabilizer, the mechanisms that underlie its therapeutic effect are unclear. Lithium has previously been shown to decrease the overall phosphorylation status of eEF2, which increases BDNF protein translation at the synapse. In this study, clinically effective doses of lithium were shown to result in antidepressant and antimanic-like effects in mice. We report that neither eEF2 kinase nor BDNF are necessary for the antidepressant effects of lithium. Additionally, eEF2 kinase is not required for the antimanic effects of lithium. However, BDNF appears to be necessary for lithium's antimanic actions. To begin to understand whether this requirement of BDNF in lithium's anti-manic action was due to synaptic changes we performed electrophysiological analysis on primary hippocampal neurons treated with lithium. Chronic lithium treatment caused a significant decrease in AMPAR-mEPSC amplitude, which requires both BDNF and its high affinity receptor, TrkB. Additionally, chronic lithium treatment caused a significant decrease in surface expression of the GluA1 subunit of the AMPAR. Collectively, this data demonstrates that BDNF is required for the antimanic effects of lithium, and that lithium's effects on the regulation of AMPARs are BDNF and TrkB dependent, which may underlie its behavioral effect.

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