The mood stabilizer lithium inhibits a select group of enzymes, including glycogen synthase kinase-3 (GSK-3). However, it is unclear if lithiums inhibition of GSK-3 is relevant for its antimanic and antidepressant effectiveness. We are utilizing biochemical, cellular, histochemical, genomic, and behavioral validation approaches to investigate whether the inhibition of GSK-3 is an integral part of the mechanism of lithiums clinical effects.? ? We are utilizing rodent behavioral models and two distinct but complementary approaches (pharmacologic inhibition and transgenic gene expression) in an attempt to further validate GSK-3 as a possible mediator of lithiums therapeutic effects. Specifically, one of the primary targets of GSK-3 is the transcription factor beta-catenin. We have shown that lithium administration to rats, in a clinically relevant paradigm, results in an increase in beta- catenin levels. We are studying the effects of both over-expression and under-expression of beta-catenin in the mouse brain as well as pharmacological mechanisms to increase beta-catenin. Using both approaches, we have found the rodents exhibit both antidepressant-like and antimanic-like behavior. Combined, these data support the hypothesis that lithium may exert its antidepressant and ? antimanic effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may represent a truly novel class of medications useful for the treatment of bipolar disorder and depression. Validation of lithiums therapeutic target will require ? clinical trials with novel inhibitors, the development of which is in progress.? It is now clear that severe mood disorders arise from abnormalities in cellular plasticity cascades that lead to aberrant information processing in critical circuits regulating mood, cognition, motor function, and neurovegetative symptomatology. In this context, it is noteworthy that GSK-3 is at the nexus of convergent neurotransmitter/ neurotrophic pathways, and demonstrates both anti-manic and antidepressant effects in mood-associated behaviors. In addition, AMPA receptor synaptic localization and phosphorylation are increased after antidepressant treatment, and decreased after treatment with anti-manic agents in vivo, therefore becoming a convergent point for therapeutic agents for mood disorders. We therefore sought to determine how GSK-3 regulates AMPA receptor trafficking and whether this mechanism is involved in mood-associated behaviors. We found that two distinct, small-molecule GSK-3 inhibitors decreased AMPA- and insulin-induced GluR1 and GluR2 internalization in cultured hippocampal neurons, suggesting that GSK-3 is involved in the regulation of AMPA receptor internalization. Treatment with AR-A014418 in mice significantly enhanced surface AMPA receptor levels in vivo in the hippocampus, but not in the frontal cortex, suggesting a regional-specific effect. The behavioral consequence of this stabilizing mechanism of GSK-3 inhibition to AMPA trafficking is under investigation. The novel mechanisms of GSK-3 regulation of AMPA receptor trafficking are anticipated to provide new mechanism for the treatment of these devastating disorders.
| de Bartolomeis, Andrea; Tomasetti, Carmine; Cicale, Maria et al. (2012) Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor. Eur Neuropsychopharmacol 22:527-35 |
| Gould, Todd D; O'Donnell, Kelley C; Picchini, Alyssa M et al. (2008) Generation and behavioral characterization of beta-catenin forebrain-specific conditional knock-out mice. Behav Brain Res 189:117-25 |
| Gould, Todd D; O'Donnell, Kelley C; Picchini, Alyssa M et al. (2007) Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium. Neuropsychopharmacology 32:1321-33 |
