Proliferative oligodendrocyte progenitor cells (OPs) express large, delayed outward-rectifying K ⁺ currents (I _K ), whereas nondividing immature and mature oligodendrocytes display much smaller I _K . Here, we show that up-regulation of I _K occurs in G ₁ phase of the cell cycle in purified cultured OPs and is the result of an RNA synthesis-dependent, selective increase of the K ⁺ channel subunit proteins Kv1.3 and Kv1.5. In oligodendrocyte cells acutely isolated from developing rat brain, a decrease of cyclin D expression is observed as these cells mature along their lineage. This is accompanied by a decrease in Kv1.3 and Kv1.5 subunit expression, suggesting a role for these subunits in the proliferative potential of OPs in situ . I _K expressed in OPs in subventricular zone and developing white matter in acutely isolated slice preparations were selectively blocked by antagonists of Kv1.3, illustrating the functional presence of this subunit in situ . Interestingly, Kv1.3 block inhibited S-phase entry of both purified OPs in culture and in tissue slice cultures. Thus, we employ both in vitro and in situ experimental approaches to show that ( i ) RNA-dependent synthesis of Kv1.3 and Kv1.5 subunit proteins occurs in G ₁ phase of the OP cell cycle and is responsible for the observed increase in I _K , and ( ii ) currents through Kv1.3-containing channels play a crucial role in G ₁ /S transition of proliferating OPs.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1—or in other genes encoding BLOC-1 subunits—in the context of the developmental model of schizophrenia pathogenesis.

Dysbindin (also known as dysbindin–1 or dystrobrevin-binding protein 1) was identified 10 years ago as a ubiquitously expressed protein of unknown function. In ...