Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β

Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, encodes a scaffold protein that has complex impacts on neuronal development. However, its role in neuronal polarization remains unclear. Here we show that phosphorylation of DISC1 at Ser58 and Ser713 regulates cortical neuron polarization¬. Expression of phosphor-dead human DISC1 (Ser58Ala, Ser713Ala; hDISC1AA) delays the transition from multipolar to uni/bipolar cells in mouse cortical culture. Mice carrying the hDISC1AA mutant exhibit aberrant orientation of the axon initial segment and reduced thickness of corpus callosum. hDISC1AA knock-in mice exhibit hyperlocomotion activity in an open field, deficits in prepulse inhibition, reduced social interaction, and defective novel object recognition. GSK3β activity is increased in the cortices of the hDISC1AA knock-in mice. Embryonic treatment of the GSK3β inhibitor SB-216763 rescues behavioral deficits in hDISC1AA/+ mice. Our findings support a model in which dual phosphorylation of DISC1 at Ser58 and Ser713 inhibits GSK3β activity and plays a crucial role in neural polarization, potentially contributing to the manifestation of psychiatric disorders related to DISC1 dysfunction.