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

Abstract

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.

AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

“…The Auts2-deficient transgenic models that have been reported display abnormal social interaction and communication deficits (16, 41–43) but also recognition memory and cued-fear associative learning impairments (41, 42). Interestingly, for the Del/+ Auts2 mice, we did not find changes in social interaction and communication.…”

“…x 8cm openings allowing access between the chambers. The protocol was similar to the one described previously (43). During the habituation phase, the tested mouse was placed in the preprint (which was not certified by peer review) is the author/funder.…”

AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders

“…Three studies were based on conditional knockout models leading to knockout of Auts2 in excitatory neurons of the forebrain 48 , in the cerebellum 22 or in developing forebrain 49 .…”

“…Three studies were based on conditional knockout models leading to knockout of Auts2 in excitatory neurons of the forebrain 48 , in the cerebellum 22 or in developing forebrain 49 . Selective deletion of Auts2 in excitatory neurons in the adult forebrain 48 induces a phenotype different from the constitutive knockout 47 .…”

“…Selective deletion of Auts2 in the cerebellum induces behavioral impairments in motor learning and vocal communications 22 . Selective deletion of Auts2 in developing forebrain led to hypoplasia of Dentate Gyrus with social deficits and stereotypies (excessive grooming and digging behaviors) 49 .…”