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

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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. <jats:italic>Dlgap2</jats:italic>, 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 <jats:italic>Dlgap2</jats:italic> loss-of-function <jats:italic>in vivo</jats:italic>, we thus generated <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>mice to investigate their phenotypes of synaptic function and social behaviors.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>The creation of <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>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 <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>mice displayed exacerbated aggressive behaviors in the resident–intruder task, and elevated social dominance in the tube test. In addition, <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. <jats:italic>Dlgap2</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our findings clearly demonstrate that <jats:italic>Dlgap2</jats:italic> 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.</jats:p> </jats:sec>