Abstract
BackgroundAs 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.MethodsThe 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.ResultsDlgap2 −/− 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.ConclusionsOur 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.
Highlights
As elegant structures designed for neural communication, synapses are the building bricks of our mental functions
Electrophysiological and ultra-structural studies, we found that Dlgap2−/−mice exhibit pronounced synaptic deficits in the orbitofrontal cortex (OFC), a brain region that plays a critical role in behavioral inhibition and regulating aggressive drives
In conclusion, our findings clearly suggest that DLGAP2 plays a crucial role in maintaining the proper functions of the OFC, a brain region that is implicated in aggressive behaviors
Summary
As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap, 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. A specialized group of synaptic macromolecules, the postsynaptic scaffolding proteins, which play a role as the master organizers of macromolecular assembly within the postsynaptic density (PSD), is pivotal to proper synaptic functions [10,11]. DLGAP2 ( known as SAPAP2 or GKAP2), as one of the main components of postsynaptic scaffolding proteins, directly interacts with DLG4 ( known as PSD-95) and SHANKs to form the DLG4-DLGAPs-SHANKs complex, which plays critical roles in synaptic morphogenesis and functions [12,13,14]. The role of Dlgap still remains elusive, which intensifies our eagerness to unveil whether Dlgap regulates social behaviors or synaptic functions
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