title: Impaired Dendritic Development and Memory in Sorbs2 Knock-Out Mice.
abstract: Intellectual disability is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning. Both environmental insults and genetic defects contribute to the etiology of intellectual disability. Copy number variations of SORBS2 have been linked to intellectual disability. However, the neurobiological function of SORBS2 in the brain is unknown. The SORBS2 gene encodes ArgBP2 (Arg/c-Abl kinase binding protein 2) protein in non-neuronal tissues and is alternatively spliced in the brain to encode nArgBP2 protein. We found nArgBP2 colocalized with F-actin at dendritic spines and growth cones in cultured hippocampal neurons. In the mouse brain, nArgBP2 was highly expressed in the cortex, amygdala, and hippocampus, and enriched in the outer one-third of the molecular layer in dentate gyrus. Genetic deletion of Sorbs2 in mice led to reduced dendritic complexity and decreased frequency of AMPAR-miniature spontaneous EPSCs in dentate gyrus granule cells. Behavioral characterization revealed that Sorbs2 deletion led to a reduced acoustic startle response, and defective long-term object recognition memory and contextual fear memory. Together, our findings demonstrate, for the first time, an important role for nArgBP2 in neuronal dendritic development and excitatory synaptic transmission, which may thus inform exploration of neurobiological basis of SORBS2 deficiency in intellectual disability.
  
  
  CONCLUSIONS
  Copy number variations of the SORBS2 gene are linked to intellectual disability, but the neurobiological mechanisms are unknown. We found that nArgBP2, the only neuronal isoform encoded by SORBS2, colocalizes with F-actin at neuronal dendritic growth cones and spines. nArgBP2 is highly expressed in the cortex, amygdala, and dentate gyrus in the mouse brain. Genetic deletion of Sorbs2 in mice leads to impaired dendritic complexity and reduced excitatory synaptic transmission in dentate gyrus granule cells, accompanied by behavioral deficits in acoustic startle response and long-term memory. This is the first study of Sorbs2 function in the brain, and our findings may facilitate the study of neurobiological mechanisms underlying SORBS2 deficiency in the development of intellectual disability.
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Qiangge
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Key Laboratory of Brain Functional Genomics (Ministry of Education and Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Xian
authors.initials: X
authors.lastname: Gao
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Li
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Center for the Unknown, Lisbon 1400-038, Portugal.
authors.forename: Catia
authors.initials: C
authors.lastname: Feliciano
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wang
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, School of Life Sciences, Peking University, Beijing 100871, China, and.
authors.forename: Dingxi
authors.initials: D
authors.lastname: Zhou
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mei
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Patricia
authors.initials: P
authors.lastname: Monteiro
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Michelle
authors.initials: M
authors.lastname: Anand
authors.affiliation: Laboratory of Behavioral Genetics, RIKEN Brain Science Institute, Wako 351-0198, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.affiliation: Key Laboratory of Brain Functional Genomics (Ministry of Education and Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Dong
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Zhanyan
authors.initials: Z
authors.lastname: Fu
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Key Laboratory of Brain Functional Genomics (Ministry of Education and Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China, Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02142, fengg@mit.edu.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000254:growth & development*; D004247:DNA / Q000235:genetics; D003712:Dendrites / Q000473:pathology*; D049229:Dendritic Spines / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D020439:Growth Cones / Q000473:pathology; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D008568:Memory; D057567:Memory, Long-Term; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D009043:Motor Activity / Q000235:genetics; D016601:RNA-Binding Proteins; D021641:Recognition, Psychology; D013216:Reflex, Startle / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; C000607590:Sorbs2 protein, mouse; D004247:DNA
keywords: Sorbs2; dendrites; dentate gyrus; intellectual disability; learning and memory; nArgBP2