期刊
MOLECULAR AUTISM
卷 5, 期 -, 页码 -出版社
BMC
DOI: 10.1186/2040-2392-5-32
关键词
Dlgap2; aggressive behavior; orbitofrontal cortex; autism; synapse; mouse model
资金
- National Science Council, Taiwan [NSC 97-3112-B-002-009, NSC 98-3112-B-002-004, NSC 99-3112-B-002-036, NSC 101-2314-B-002-136-MY3]
- National Taiwan University Hospital [NTUH 100-S1525]
- National Taiwan University (AIM for Top University Excellent Research Project) [10R81918-03101R892103, 102R892103]
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.
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