Gauthier and colleagues report additional genetic evidence supporting “synapse” pathology for schizophrenia. They discovered two de novo mutations in SHANK3, which encodes a scaffold protein in the post-synaptic density of excitatory synapses. The first mutation is a nonsense mutation (R1117X) in a patient with schizophrenia and his two brothers with schizophrenia and schizoaffective disorder. The second mutation is a missense mutation (R536W) in a patient with schizoaffective disorder. Furthermore, the effect of both mutations in SHANK3 was functionally tested in vivo and in vitro with zebrafish behavior and rat hippocampal neuronal culture. The impairment of swimming activity by the morpholino-mediated knockdown of the ortholog of SHANK3 was partially rescued by the R536W mutant, and was not rescued by the R1117X mutant. Overexpression of wild-type SHANK3 and the R536W mutant stimulate neurite outgrowth in rat hippocampal neurons, but the R1117X mutant does not. These findings, taken together, lead the authors to conclude that the R1117X mutation has a loss-of-function...  Read more

Gauthier and colleagues report additional genetic evidence supporting “synapse” pathology for schizophrenia. They discovered two de novo mutations in SHANK3, which encodes a scaffold protein in the post-synaptic density of excitatory synapses. The first mutation is a nonsense mutation (R1117X) in a patient with schizophrenia and his two brothers with schizophrenia and schizoaffective disorder. The second mutation is a missense mutation (R536W) in a patient with schizoaffective disorder. Furthermore, the effect of both mutations in SHANK3 was functionally tested in vivo and in vitro with zebrafish behavior and rat hippocampal neuronal culture. The impairment of swimming activity by the morpholino-mediated knockdown of the ortholog of SHANK3 was partially rescued by the R536W mutant, and was not rescued by the R1117X mutant. Overexpression of wild-type SHANK3 and the R536W mutant stimulate neurite outgrowth in rat hippocampal neurons, but the R1117X mutant does not. These findings, taken together, lead the authors to conclude that the R1117X mutation has a loss-of-function effect.

Although their findings may only account for rare cases of the disease condition, it is expected that their findings will be replicated in different populations. Such rare de novo or inheritance mutations, however, may have a strong biological impact, and they are useful to address potential molecular disease pathways. Given that SHANK3, at the synaptic region, is known to interact, or potentially interacts, with other genetic risk factors for schizophrenia and autism, such as neurexin-1, neuroligin-3, and -4, neuregulin-1, ErbB4, and DISC1, the convergence of synaptic signaling disturbances may account for the pathophysiologies of these devastating conditions. The question that arises is how such genetic disturbances lead to a wide range of mental disorders, such as schizophrenia and autism, which are sometimes complicated by mental retardation. Could other genetic risks and/or environmental factors define the final disease phenotypes? How can we address this question by utilizing animal models? The typical onset of schizophrenia is in late adolescence or early adulthood, whereas patients with autism are usually first diagnosed in early childhood. The different time courses of schizophrenia and autism should be considered in animal studies at the molecular, neuronal circuit, and behavioral levels.