Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Lithium directly inhibits GSK3 (glycogen synthase kinase 3), a critical regulator of multiple signal transduction pathways. Inhibition of GSK3 provides a compelling explanation for many of the known effects of lithium, including effects on early development and insulin signalling/glycogen synthesis. However, lithium also inhibits inositol monophosphatase, several structurally related phosphomonoesterases, phosphoglucomutase and the scaffolding function of β-arrestin-2. It is not known which of these targets is responsible for the behavioural or therapeutic effects of lithium in vivo. The present review discusses basic criteria that can be applied to model systems to validate a proposed direct target of lithium. In this context, we describe a set of simple behaviours in mice that are robustly affected by chronic lithium treatment and are similarly affected by structurally diverse GSK3 inhibitors and by removing one copy of the Gsk3b gene. These observations, from several independent laboratories, support a central role for GSK3 in mediating behavioural responses to lithium.
Skip Nav Destination
Conference Article| September 21 2009
Validating GSK3 as an in vivo target of lithium action
W. Timothy O'Brien;
Peter S. Klein
Peter S. Klein 1
1Room 364, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
1To whom correspondence should be addressed (email firstname.lastname@example.org).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received: May 27 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
W. Timothy O'Brien, Peter S. Klein; Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans 1 October 2009; 37 (5): 1133–1138. doi: https://doi.org/10.1042/BST0371133
Download citation file:
Don't already have an account? Register
Get Access To This Article
Buy This Article