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

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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Furthermore, rare de novo CNVs, deletions and duplications in genes encoding SHANK interacting proteins such as Disk large-associated protein 2 (DLGAP2) have been associated with ASD 64,[189][190][191][192] . In line with SHANK mice models, Dlgap2 -/-mice show reduced spine density and a downregulation of synaptic proteins such as HOMER1 193 .…”

Autism Spectrum Disorders: Translating human deficits into mouse behavior

“…Dlgap2 -/-mice, lacking a main component of the post-synaptic density, showed enhanced aggressive behavior towards the intruder, which may explain their enhanced social approach (Jiang-Xie et al, 2014a). On the other hand, Pten +/-or En2 -/-male mice present decreased sociability and less aggression Page, 2014, 2015).…”

Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7

“…The total dendritic length and the number of dendritic branches per neuron were measured and analyzed as described previously using NeuronJ, a plugin for ImageJ (NIH) (Popko et al, 2009). For analysis of dendritic spine density and area, spines along two secondary and tertiary dendritic segments (20 µm long) from each neuron were selected as described (Jiang-Xie et al, 2014), and they were counted and measured using MetaMorph (Molecular Devices, USA) (Ma et al, 2008b). All the data were analyzed by an experimenter blind to the groups.…”