The Role Of COUP-TFI Gene In Development Of Ventral Telencephalon And Cortical Interneurons

Human cerebrum is the most hierarchical region in the central nervous system to control cognition,consciousness,language and behavior.The cerebral cortex comprises of excitatory projection neurons and inhibitory interneurons,which interact with each other to maintain the excitatory-inhibitory balance,and to ensure the appropriate function of the cortex.The disruption of inhibitory circuits in the cortex is highly associated with neural diseases such as schizophrenia,autism spectrum disorders and epilepsy.However,so far the molecular mechanisms how the cortical interneurons are generated,and how the defects in the development and the function of the cortical interneurons cause neural development associated diseases remain largely unknown.COUP-TFI gene mutations result in epilepsy,intellectual disorders,or autism spectrum disorders in human.The studies in mouse have demonstrated that COUP-TFI gene is one of the most important regulatory genes participating in the dorsal telencephalon patterning and the differentiation of the cortical projection neurons.However,whether and how COUP-TFI gene is involved in the ventral telencephalon patterning and the differentiation of the cortical interneurons hasn't been clearly elucidated.In this study,we found that in embryonic ventral telencephalon,COUP-TFI gene is expressed highest in the ventricular zone,where resides neural stem cells.By using RXCre mouse,we established the ventral telencephalonspecificCOUP-TFIgeneconditionalknockout(RXCre/+;COUP-TFI^flox/flox)mouse successfully.We observed that the development of striatum and hippocampus is abnormal,and the cortical interneurons especially Parvalbumin⁺and Somatostatin⁺interneurons originated from medial ganglionic eminence?MGE?are significantly decreased in the adult COUP-TFI mutant mice.Furthermore,comparing with the control,the miniature inhibitory postsynaptic currents?mIPSCs?,recorded from the layer IV projection neurons exhibit a decrease in the frequency in the mutant,indicating the decreased GABAergic inhibitory activities.RNA-seq analysis revealed that in the mutant MGE,the expression of a few genes,involved in the neural development or neural development associated diseases,is downregulated.Our study demonstrates that COUP-TFI gene participates in the regulation of the ventral telencephalon patterning and the development of cortical interneurons.Our findings will benefit not only the understanding of the development of cortical interneurons,but also the understanding of the etiology of neural development associated diseases such as intellectual disorders,epilepsy,autism spectrum disorders,and schizophrenia.