Modeling GABAergic Interneuron Deficits In Down Syndrome Using Patient IPSCs

Down syndrome(DS)is the most common genetic disorder of intellectual impairment and is caused by trisomy of chromosome 21.Although DS patient exhibit reduced brain size and diminished GABA transmitter from fetal tissue and postmortem studies,the precise cellular and developmental mechanisms of cognitive disorder in DS remain unclear.Patient induced pluripotent stem cells(iPSCs)provide an opportunity to uncover human developmental disorders.Here,we differentiated iPSCs derived from DS patients into forebrain GABA interneurons.Compared to the disomy iPSC control,the DS GABA interneurons demonstrated defects of neuronal morphological complexity in vitro.To discern the cellular behaviors of DS GABA interneurons in vivo,we further transplanted these GABAergic progenitors into medial septum of SCID mice.After six months of transplantation,the transplanted DS iPSCs generated GABA interneurons similarly with disomy iPSCs in vivo.However,we found DS GABA interneurons had a reduction of neural soma size,shorter neurites,and less dendritic complexity in the graft and adjacent area.Furthermore,the differentiation fate of DS GABA interneuron subtypes was altered.The DS GABA progenitors tend to generate more SST+ but fewer CR+ GABA interneurons in the comparison with disomy cells.Moreover,DS GABA interneurons exhibit impaired migration and neurite projection along septohippocampal pathway and in hippocampus.These results suggest the abnormal development of DS GABA interneurons may connect to the diminished GABA transmitter and reduced brain size in DS patients,explaining the reduced brain size and impaired cognition,at least partly.Our study illustrated pathological features of DS and offered a novel model to study the mechanisms of Down syndrome.