DISCI knockdown impairs the tangential migration of cortical interneurons by affecting the actin cytoskeleton

Disrupted-in-Schizophrenia 1 (DISCI) is a risk gene for a spectrum of major mental disorders. It has been shown to regulate radial migration as well as dendritic arborization during neurodevelopment and corticogenesis. In a previous study we demonstrated through in vitro experiments that DISCI also controls the tangential migration of cortical interneurons originating from the medial ganglionic eminence (MGE). Here we first show that DISCI is necessary for the proper tangential migration of cortical interneurons in the intact brain. Expression of EGFP under the Lhx6 promotor allowed us to analyze exclusively interneurons transfected in the MGE after in utero electroporation. After 3 days in utero, DISCI deficient interneurons displayed prolonged leading processes and, compared to control, fewer neurons reached the cortex. Time-lapse video microscopy of cortical feeder-layers revealed a decreased migration velocity due to a reduction of soma translocations. lmmunostainings indicated that DISCI is co-localized with F-actin in the growth cone-like structure of the leading process. DISCI knockdown reduced F-actin levels whereas the overall actin level was not altered. Moreover, DISCI knockdown also decreased levels of phosphorylated Girdin, which cross-links F-actin, as well as the Girdin-activator pAkt. In contrast, using time-lapse video microscopy of fluorescence-tagged tubulin and EB3 in fibroblasts, we found no effects on microtubule polymerization when DISCI was reduced. However, DISCI affected the acetylation of microtubules in the leading processes of MGE-derived cortical interneurons. Together, our results provide a mechanism how DISCI might contribute to interneuron migration thereby explaining the reduced number of specific classes of cortical interneurons in some DISCI mouse models.