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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Molecular Autism 1/2014

Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits

Zeitschrift:
Molecular Autism > Ausgabe 1/2014
Autoren:
Li-Feng Jiang-Xie, Hsiao-Mei Liao, Chia-Hsiang Chen, Yuh-Tarng Chen, Shih-Yin Ho, Dai-Hua Lu, Li-Jen Lee, Horng-Huei Liou, Wen-Mei Fu, Susan Shur-Fen Gau
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​2040-2392-5-32) contains supplementary material, which is available to authorized users.
Li-Feng Jiang-Xie, Hsiao-Mei Liao, Chia-Hsiang Chen contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SSG initiated and guided this research. SSG, HML and CHC created and verified the mutant mouse. LFJX, YTC and WMF designed the experiments in this paper. LFJX, YTC, DHL and SYH executed the experiments and analyzed the data. LFJX, YTC, DHL, SYH, HHL, LJL, WMF and SSG interpreted the results. LFJX prepared the first draft. HML, CHC, SYH, YTC, WMF and SSG revised the manuscript. HML, WMF and SSG revised the manuscript according to reviewers’ comments. SSG prepared the final files for submission. All authors approved the final version.

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.
Zusatzmaterial
Additional file 1: Figure S1: Body weight and shape of Dlgap2 +/+ (WT) and Dlgap2 -/- (KO) mice. Figure S2. The mEPSC frequency of Dlgap2 Dlgap2 +/+ (WT) and Dlgap2 -/- (KO) mice. (DOCX 843 KB)
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Literatur
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