Abstract
Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)R451C mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3R451C mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3R451C mice. We report that NL3R451C mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3R451C mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3R451C mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3R451C mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.
Highlights
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder diagnosed by impaired social interaction, repetitive behavior and/or restrictive interests
Synaptic currents were recorded from pyramidal-like neurons of the amygdala in the NL3R451C and WT littermate controls
To determine if behavioral phenotypes including aggression caused by the R451C mutation penetrate across background strains we examined a range of behavioral outputs in WT and NL3R451C mice bred on a pure C57Bl/6 background strain
Summary
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder diagnosed by impaired social interaction, repetitive behavior and/or restrictive interests. Multiple comorbid traits are commonly observed including hyperactivity, increased anxiety and aggressive behavior (Argyropoulos et al, 2013; Burrows et al, 2015; Farmer et al, 2015). A significant number of patients with ASD are drug refractory for aggressive behaviors (Farmer et al, 2015). Aggressive behavior in ASD limits patient access to education, healthcare and employment and is one of the strongest predictors for admission to institutions (Lakin et al, 1983) and poor quality of life among individuals with developmental disabilities (Gardner and Moffatt, 1990). The neurobiological mechanisms underlying aggression are not fully characterized, changes in neural activity within the amygdala and connectivity between the amygdala and other brain regions may contribute to these behaviors (Varkevisser et al, 2017; Buades-Rotger et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
