Inversed Effects of Nav1.2 Deficiency at Medial Prefrontal Cortex and Ventral Tegmental Area for Prepulse Inhibition in Acoustic Startle Response.

Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric disorders including schizophrenia. However, pathological mechanisms for the schizophrenia-relevant behavioral abnormalities caused by the variants remain poorly understood. Here in this study, we characterized mouse lines with selective Scn2a deletion at schizophrenia-related brain regions, medial prefrontal cortex (mPFC) or ventral tegmental area (VTA), obtained by injecting adeno-associated viruses (AAV) expressing Cre recombinase into homozygous Scn2a-floxed (Scn2afl/fl) mice, in which expression of the Scn2a was locally deleted in the presence of Cre recombinase. The mice lacking Scn2a in the mPFC exhibited a tendency for a reduction in prepulse inhibition (PPI) in acoustic startle response. Conversely, the mice lacking Scn2a in the VTA showed a significant increase in PPI. We also found that the mice lacking Scn2a in the mPFC displayed increased sociability, decreased locomotor activity, and increased anxiety-like behavior, while the mice lacking Scn2a in the VTA did not show any other abnormalities in these parameters except for vertical activity which is one of locomotor activities. These results suggest that Scn2a-deficiencies in mPFC and VTA are inversely relevant for the schizophrenic phenotypes in patients with SCN2A variants.

Oscillation of Cdc20-APC/C-mediated CAMDI stability is critical for cortical neuron migration.

Radial migration during cortical development is required for formation of the six-layered structure of the mammalian cortex. Defective migration of neurons is linked to several developmental disorders such as autism and schizophrenia. A unique swollen structure called the dilation is formed in migrating neurons and is required for movement of the centrosome and nucleus. However, the detailed molecular mechanism by which this dilation forms is unclear. We report that CAMDI, a gene whose deletion is associated with psychiatric behavior, is degraded by cell division cycle protein 20 (Cdc20)-anaphase-promoting complex/cyclosome (APC/C) cell-cycle machinery after centrosome migration into the dilation in mouse brain development. We also show that CAMDI is restabilized in the dilation until the centrosome enters the dilation, at which point it is once again immediately destabilized. CAMDI degradation is carried out by binding to Cdc20-APC/C via the destruction box degron of CAMDI. CAMDI destruction box mutant overexpression inhibits dilation formation and neuronal cell migration via maintaining the stabilized state of CAMDI. These results indicate that CAMDI is a substrate of the Cdc20-APC/C system and that the oscillatory regulation of CAMDI protein correlates with dilation formation for proper cortical migration.