**6. GSK3, DISC1 and mood disorders**

GSK3's involvement in the Wnt pathway is also regulated by the scaffolding protein DISC1. This protein directly binds to GSK3 to inhibit phosphorylation of β-catenin, preventing its degradation and activating its transcriptional activity [38]. This promotes NPC proliferation during embryonic development and in the adult brain. Depletion of DISC1 or expression of DISC1 mutants associated with mood disorders and schizophrenia reduced NPC proliferation and induced schizophrenia and depression-like symptoms in mice [38, 73]. These defects were normalized by administration of pharmacological inhibitors of GSK3. These studies demon‐ strate that DISC1 is a negative regulator of the Wnt pathway and NPC proliferation by directly inhibiting GSK3-mediated phosphorylation of β-catenin. Interestingly, one schizophreniaassociated mutant of DISC1 (S704C) did not affect GSK3 activity, Wnt signaling or NPC proliferation, but instead impaired neuronal migration in the developing cortex via reduced binding to cytoskeletal proteins (Dixdc1) [73]. Elsewhere, it was shown that DISC1 acts as a molecular switch between proliferation and migration in NPC's, whereby DISC1 inhibits GSK3-mediated phosphorylation of β-catenin and activates its transcriptional activity to drive proliferation of NPC's, while in committed, post-mitotic neurons, DISC1 regulates neuronal migration via another protein called BBS1 and the centrosome [74]. Together, these studies demonstrate that DISC1 regulates NPC proliferation and neuronal migration through GSK3 dependent and independent pathways, respectively.

As well as DISC1, other upstream regulators of GSK3 are genetically linked to mood disorders and schizophrenia, including Akt [75], Neuregulin [76] and the dopamine/β-arrestin signaling complex [77, 78]. GSK3 kinase activity is also inhibited by several mood-stabilizers, antidepressants and anti-psychotic drugs [6, 79, 80], while genetic manipulation of GSK3 activity in mice produces behaviours correlating with mood disorders [24-28]. A single nucleotide polymorphism in the promoter region of GSK3β has also been correlated with onset of Bipolar disorder [81]. Together, these observations strongly implicate elevated GSK3 activity in the etiology of mood disorders and schizophrenia. Neurogenesis is decreased in these disorders [82, 83], but is promoted by mood stabilizing drugs, such as lithium [84, 85]. Therefore, moodstabilizing drugs may act (at least in part) by promoting neurogenesis via inhibition of GSK3. If so, promoting neurogenesis using GSK3 inhibitors could also be beneficial to other mental disorders, including neurodegenerative diseases such as Alzheimer's disease and age-related cognitive decline, as well repair following brain injury, such as stroke and spinal chord injuries.
