MODULATION OF NEUROTROPIC SIGNALING CASCADES BY MOOD STABILIZING AGENTS

studies is showing that severe mood disorders are associated with reductions in

regional CNS volume as well as reductions in the numbers and /or sizes of

neurons and glia; these observations suggest that while mood disorders have

traditionally been conceptualized as neurochemical disorders, they may, in fact,

be disorders of structural plasticity as well.  It is thus noteworthy that

the two structurally highly dissimilar mood stabilizing agents lithium and

valproate (VPA) indirectly regulate a number of factors involved in cell

survival pathways, including CREB, BDNF, bcl-2 and MAP kinases, and may thus

bring about some of their delayed long term beneficial effects via

underappreciated neurotropic factor like signaling.  In this context,

chronic lithium and VPA administration robustly increases the levels of the

cytoprotective protein bcl-2 in critical areas of rodent brain, including

frontal cortex, and hippocampus.  Consistent with the robust increases in

bcl-2 levels, lithium and VPA exert neuroprotective effects in a variety of

paradigms. Lithium also produces a ~ 25% increase in the number of newborn cells

in the dentate gyrus with ~ 65% of the newborn cells expressing neuronal

markers.  In contrast to BcL-2, BAD (Bcl-2 antagonist of cell death) is a

major pro-apoptotic protein, and is inactivated by phosphorylation at

ser112 by the ribosomal S6 kinase (RSK) and a mitochondrial-localized

cAMP-dependent kinase (PKA).  Notably, both chronic lithium and VPA

treatment increase pBAD (ser112) levels in rodent brain, effects which are

accompanied by increased levels of activated RSF.  In SH-SY5Y cells, VPA

activates ERK MAP kinases, and VPA’s effects on RSK and BAD are markedly

attenuated by blockage of ERK signaling. Taken together, the data indicate that

mood-stabilizers, like many endogenous neurotrophins, may promote neuronal

survival and plasticity via both transcriptional and post-transcriptional

mechanisms, which allow for the coordinated regulation of the activity and

actions of both lithium and VPA at therapeutically relevant concentrations is

the glycogen synthase kinase 3ß (GSK-3ß) pathway.  While GSK-3ß does

regulate a variety of cellular and physiological processes, its regulation of

neurotrophic cascades and modulation of circadian rhythms may be especially

important for the treatment of mood disorders.  To date, while there is

suggestive evidence that Wnt/GSK-3ß regulation may be related to BD treatment

efficacy, there is no direct evidence that abnormalities of this pathway are

present in BD.  Recently, small molecule GSK-3ß inhibitors that may cross

the blood brain barrier have been developed; these molecules have been used

successfully to protect neuronal cells from toxic stimuli in culture. 

Future research should examine these molecules for efficacy in the treatment of

BD. Even more promising may be the development of drugs that, similar to FRAT1,

inhibit GSK-3ß mediated phosphorylation of specific substrates (e.g. unprimed

substrates such as ß-catenin and axin) but not substrates requiring

pre-phosphorylation, such as glycogen synthase, thus being specific for the

Wnt-mediated effects of this multi-talented enzyme.  This approach may make

it possible to discern which GSK-3ß pathway is particularly relevant for the