Auts2 deletion involves in DG hypoplasia and social recognition deficit: The developmental and neural circuit mechanisms

The involvement of genetic risk and the underlying developmental and neural circuit mechanisms in autism-related social deficit are largely unclear. Here, we report that deletion of AUTS2, a high-susceptibility gene of ASDs, caused postnatal dentate gyrus (DG) hypoplasia, which was closely relevant to social recognition deficit. Furthermore, a previously unknown mechanism for neural cell migration in postnatal DG development was identified, in which Auts2-related signaling played a vital role as the transcription repressor. Moreover, the supramammillary nucleus (SuM)-DG-CA3 neural circuit was found to be involved in social recognition and affected in Auts2-deleted mice due to DG hypoplasia. Correction of DG-CA3 synaptic transmission by using a pharmacological approach or chemo/optogenetic activation of the SuM-DG circuit restored the social recognition deficit in Auts2-deleted mice. Our findings demonstrated the vital role of Auts2 in postnatal DG development, and this role was critical for SuM-DG-CA3 neural circuit-mediated social recognition behavior.

Automated summary

The involvement of the high-susceptibility gene AUTS2 in social recognition deficit related to autism spectrum disorders (ASDs) is determined. It is found that deletion of AUTS2 leads to postnatal dentate gyrus development impairment and affects the Supramammillary nucleus-Dentate Gyrus-CA3 (SuM-DG-CA3) neural circuit, resulting in social recognition deficit. Additionally, a previously unknown mechanism of neural cell migration in postnatal dentate gyrus development, related to Auts2 signaling as a transcription repressor, is identified. The correction of the DG-CA3 synaptic transmission or activation of the SuM-DG circuit restores the social recognition deficit in Auts2-deleted mice.