Behavioral Characterization of SLIT3 Knock-out Mice: SLIT3 Implications in ASD

Background:  Altered neuronal connectivity is a potential neural signature of Autism Spectrum Disorder (ASD). Slit/Robo signaling plays an important role in axon guidance, cell migration and dendritic spine formation, which is involved in the development of neuronal connectivity and structure. Indeed, Slit/Robo signaling has been implicated in the pathophysiology of ASD, as altered expression level of Slits or Robo receptors is observed in some individuals with autism. Furthermore, a genetic variant of SLIT3, one of genes encoding Slits, was found in individuals with ASD. Nevertheless, a direct relationship between SLIT3 mutation and autism associated behaviors has not been examined.

Objectives: The purpose of the current study is to investigate how SLIT3 mutation affects a variety of behavioral domains associated with autism in mice.

Methods: In order to characterize behavioral changes resulting from SLIT3 mutation, we examined two to four month old male and female SLIT3 knockout (KO) mice for locomotive, emotional, social, and cognitive behaviors using the open field, three chamber social, and novel object recognition tests.

Results: SLIT3 KO mice were observed to travel significantly shorter distances than WT mice in the open field test. In addition, female KO mice tended to spend shorter time in the center area of the open field when compared to the respective controls. Interestingly, KO mice were not different from the controls in social approach behavior and object recognition memory tests.

Conclusions: The reduced activity of SLIT3 KO mice in the open field test indicates that the KO mice are hypo-locomotive. The heightened tendency to avoid center area of the open field shown only in the female KO mice suggests that the deletion of SLIT3 induces a sex-specific anxiety. These findings suggest that SLIT3 may be involved in the formation of neural circuits that regulate locomotion and anxiety rather than social or cognitive behaviors.