Larimore Jennifer, Zlatic Stephanie A, Arnold Miranda, Singleton Kaela S, Cross Rebecca, Rudolph Hannah, Bruegge Martha V, Sweetman Andrea, Garza Cecilia, Whisnant Eli, Faundez Victor
Department of Biology, Agnes-Scott College, Decatur, GA, USA.
Department of Cell Biology, Emory University, Atlanta, GA, USA.
Front Genet. 2017 Mar 10;8:28. doi: 10.3389/fgene.2017.00028. eCollection 2017.
The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders. Here we define the transcriptome of developing wild type and dysbindin null mouse hippocampus in order to identify mechanisms downstream dysbindin defects. The dysbindin mutant transcriptome revealed previously reported GABA parvalbumin interneuron defects. However, the transcriptome additionally uncovered changes in the expression of molecules controlling cellular excitability such as the cation-chloride cotransporters NKCC1, KCC2, and NCKX2 as well as the potassium channel subunits Kcne2 and Kcnj13. Our results suggest that dysbindin deficiency phenotypes, such as GABAergic defects, are modulated by the expression of molecules controlling the magnitude and cadence of neuronal excitability.
神经发育因子失调结合蛋白是突触功能和γ-氨基丁酸（GABA）中间神经元发育所必需的。精神分裂症患者海马体中的失调结合蛋白水平降低。小鼠失调结合蛋白基因缺陷以及其他神经发育障碍的小鼠模型都存在GABA能神经传递缺陷，并且在某些情况下，小清蛋白阳性中间神经元表型缺失。这表明失调结合蛋白缺乏的下游机制，比如那些影响GABA中间神经元的机制，可能为导致或改善各种神经发育障碍的途径提供信息。在这里，我们定义了发育中的野生型和失调结合蛋白缺失小鼠海马体的转录组，以确定失调结合蛋白缺陷的下游机制。失调结合蛋白突变体的转录组揭示了先前报道的GABA小清蛋白中间神经元缺陷。然而，该转录组还发现了控制细胞兴奋性的分子表达变化，如阳离子-氯离子共转运体NKCC1、KCC2和NCKX2，以及钾通道亚基Kcne2和Kcnj13。我们的结果表明，失调结合蛋白缺乏的表型，如GABA能缺陷，受到控制神经元兴奋性大小和节奏的分子表达的调节。
