The causes of the heightened susceptibility of young people to several prevalent psychiatric diseases, such as mood disorders, remain largely unknown (4
). This problem is of increasing importance because of the rapidly growing number of young people diagnosed with psychiatric disorders and the associated rising numbers of psychotropic medications prescribed for them (2
). This study examined GSK3 in developing mouse brain to address the possibility that developmental changes in GSK3 may be linked to heightened susceptibility to psychiatric diseases in the young. This hypothesis was based on much evidence from pre-clinical, clinical, and genetic studies that dysregulated GSK3 likely increases susceptibility to mood disorders as well as other psychiatric diseases (26
), and that GSK3 is inhibited by mood stabilizers, antidepressants, and atypical antipsychotics (11
). The results show that the brain levels and regulation of GSK3 undergo large fluctuations during development and that lithium- and fluoxetine-induced inhibitory serine-phosphorylation of GSK3 are blunted in young compared with adult mouse brain.
GSK3 levels were generally higher in the brains of young mice than adult mice until approximately six to eight weeks of age. One day after birth, the levels of GSK3α and GSK3β were ~1.8-fold higher than adult levels in the cerebral cortex, and hippocampal GSK3β, but not GSK3α, was two-fold adult levels. With the exception of hippocampal GSK3α, the brain region levels of GSK3 subsequently increased, reaching peak levels in juveniles two to three weeks after birth which were nearly four-fold higher than adult levels. These results extend the report by Leroy and Brion (29
) that GSK3β levels are higher in whole brain of young mice than adults.
High brain levels of GSK3 in young mice raise the possibility that mood regulation during development may be more sensitive to disruption than adult brain in response to impairments in the inhibitory control of GSK3. For example, serotonin and brain-derived neurotrophic factor (BDNF) normally contribute to maintaining inhibitory control of GSK3 in the brain (15
), and each may be deficient in depression (33
). Disruptions in the inhibition of GSK3 due to depression-associated deficits in BDNF or serotonin may contribute to dysregulated GSK3 and susceptibility to mood disorders (28
), which may be accentuated in developing brains. Thus, a moderate 25% increase in GSK3 activity in adults due to these deficiencies would be four-fold greater in young mice that express four times greater brain levels of GSK3. Previous studies have indicated that elevated GSK3 is not alone sufficient to cause depression, but heightens vulnerability to stress-induced depression-like behavior and is a major target of lithium's effects in mice (25
), These findings raise the possibility that high GSK3 levels during development may contribute to the heightened susceptibility of young people to mood disorders and other psychiatric diseases that involve dysregulated GSK3.
The regulatory serine and tyrosine phosphorylation of GSK3 were also examined in mouse brain regions during development. The inhibitory serine-phosphorylation of GSK3, particularly GSK3β, was remarkably high in one day postnatal mouse brain. This modification inhibits GSK3 in all known signaling pathways except for the Wnt pathway that regulates β-catenin, which functions independently of GSK3 serine-phosphorylation (6
). Thus, the high serine-phosphorylation of GSK3 at one day postnatal age may serve to allow normal Wnt signaling, which is critical for brain development (36
), while inhibiting other actions of GSK3. The signal causing the early high serine-phosphorylation of GSK3 remains unidentified. Although Akt, a common mediator of GSK3 serine-phosphorylation, exhibited high levels in young mouse brain and was highly phosphorylated on its activating residues at one day postnatal compared with adult brain, it remained highly active at two and three weeks of age; ages when the serine-phosphorylation of GSK3 fell precipitously. In comparison, the signaling kinases ERK1/2, p38, and JNK displayed different developmental patterns of change in levels and phosphorylation. Compared with GSK3 serine-phosphorylation, the tyrosine phosphorylation of GSK3 was relatively stable during development, although it was notably low for one isoform of GSK3 in each brain region examined in young mice. Differences between GSK3α and GSK3β in both serine- and tyrosine-phosphorylation during development highlight growing evidence for differences in the regulation and functions of these two isoforms of GSK3 (6
Since increasing numbers of young people are being treated with mood stabilizers and antidepressants, it is important to determine if the actions of these drugs differ with age. Both lithium and fluoxetine cause large increases in the inhibitory serine-phosphorylation of GSK3 in adult mouse brain (13
), actions that may contribute to their therapeutic actions as a mood stabilizer and antidepressant, respectively. However, as opposed to adult mice, administration of each of these drugs to young mice had very blunted effects on the serine-phosphorylation of GSK3. Although examining specific ages of mice necessitated studying acute responses—rather than the effects of chronic treatments that are required for therapeutic effects— and these findings suggest that the signaling mechanisms mediating increased serine-phosphorylation of GSK3 induced by lithium and fluoxetine differ in young and adult mouse brain.
GSK3 regulates many crucial neuronal processes, acting as an integrator of several major signaling pathways linked to neurotransmitter receptors, hormones, and growth factors (6
). Impairments in these signaling systems that converge on GSK3, such as deficient serotonergic activity, reduce the inhibitory control of GSK3. In the young, the high levels of GSK3 and the age-related large fluctuations in levels and regulatory phosphorylation of GSK3 may create an unstable condition that is especially susceptible to imbalance by environmental and genetic influences. Furthermore, the diminished capacities of lithium and fluoxetine to increase the inhibitory serine-phosphorylation of GSK3 raise the possibility that in the young mechanisms controlling GSK3 and pharmacological control of GSK3 may differ from adults.