Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood1–10. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons. Unphosphorylated DISC1 regulates canonical Wnt signaling via an interaction with GSK3β, whereas specific phosphorylation at Serine 710 (S710) triggers the recruitment of Bardet-Biedl-Syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, while DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, while a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and suggest that phosphorylation of this protein at S710 activates a key developmental switch.

Neuregulin 3 (NRG3) is a paralog of NRG1. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, and several intronic single nucleotide polymorphisms in NRG3 are associated with delusions in patients with schizophrenia. In order to gain insights into the biological function of the gene, we generated a novel Nrg3 knockout (KO) mouse model and tested for neurobehavioral phenotypes relevant to psychotic disorders. KO mice displayed novelty-induced hyperactivity, impaired prepulse inhibition of the acoustic startle response, and deficient fear conditioning. No gross cytoarchitectonic or layer abnormalities were noted in the brain of KO mice. Our findings suggest that deletion of the Nrg3 gene leads to alterations consistent with aspects of schizophrenia. We propose that KO mice will provide a valuable animal model to determine the role of the NRG3 in the molecular pathogenesis of schizophrenia and other psychotic disorders.

Schizophrenia (SZ) is often described as a disease of neuronal connectivity. Cognitive processes such as working memory, which are particularly dependent on the proper functioning of complex cortical circuitry, are disturbed in the disease. Reciprocal connections between pyramidal neurons and interneurons, as well as dopaminergic innervations, form the basis for higher cognition in the cortex. Nonetheless, only a few review articles are available which address how each synapse operates, and is possibly disturbed in SZ, at least in part by mechanisms involving genetic susceptibility factors for SZ. In this review, we provide an overview of cortical glutamatergic, GABAergic, and dopaminergic circuitry, review SZ-associated deficits at each of these synapses, and discuss how genetic factors for SZ may contribute to SZ-related phenotypes deficits in a synapse-specific manner. Pinpointing the spatially and temporally distinct sites of action of putative SZ susceptibility factors may help us better understand the pathological mechanisms of SZ, especially those associated with synaptic functioning and neuronal connectivity.

L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor co-agonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.