title: Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits.
abstract: BACKGROUND
  As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors.
  
  
  METHODS
  The creation of Dlgap2 (-/-) mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident-intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 (-/-) mice.
  
  
  RESULTS
  Dlgap2 (-/-) mice displayed exacerbated aggressive behaviors in the resident-intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 (-/-) mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 (-/-) mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC.
  
  
  CONCLUSIONS
  Our findings clearly demonstrate that Dlgap2 plays a vital role in social behaviors and proper synaptic functions of the OFC. Moreover, these results may provide valuable insights into the neuropathology of autism.
authors: Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.|Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.
authors: Li-Feng
authors: LF
authors: Jiang-Xie
authors: Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.
authors: Hsiao-Mei
authors: HM
authors: Liao
authors: Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.|Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.|Department and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors: Chia-Hsiang
authors: CH
authors: Chen
authors: Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.
authors: Yuh-Tarng
authors: YT
authors: Chen
authors: Department of Pharmacology, School of Medicine, College of Medicine, National Taiwan University, 11F No.1 Sec. 1, Ren-Ai Road, Taipei 10051, Taiwan.
authors: Shih-Yin
authors: SY
authors: Ho
authors: Department of Pharmacology, School of Medicine, College of Medicine, National Taiwan University, 11F No.1 Sec. 1, Ren-Ai Road, Taipei 10051, Taiwan.
authors: Dai-Hua
authors: DH
authors: Lu
authors: Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.|Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Li-Jen
authors: LJ
authors: Lee
authors: Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.|Department of Pharmacology, School of Medicine, College of Medicine, National Taiwan University, 11F No.1 Sec. 1, Ren-Ai Road, Taipei 10051, Taiwan.
authors: Horng-Huei
authors: HH
authors: Liou
authors: Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.|Department of Pharmacology, School of Medicine, College of Medicine, National Taiwan University, 11F No.1 Sec. 1, Ren-Ai Road, Taipei 10051, Taiwan.
authors: Wen-Mei
authors: WM
authors: Fu
authors: Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.|Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.
authors: Susan Shur-Fen
authors: SS
authors: Gau
keywords: Dlgap2; aggressive behavior; mouse model; orbitofrontal cortex, autism; synapse