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

Abstract

The Human 1.2-MbAUTS2locus on chromosome 7q11.22 encodes a 1259-aa full-length protein, and a 711-aa C-terminal isoform. Functions of these AUTS2 proteins are only partly known. The major traits found in patients displaying AUTS2 locus mutations are Intellectual Disabilities, microcephaly attention deficit hyperactivity disorder (ADHD) (54%), and autistic traits. Furthermore,AUTS2common variants were recently found associated to alcohol consumption and dyslexia using GWAS approaches. Auts2 localizes mainly in cell nuclei. We evidenced by super-resolution that Auts2 is present in dendritic spines. Auts2 interacts with Ttc3, the Akt2 E3 ligase, and negatively regulates Akt2 ubiquitination. Auts2 haploinsufficiency affects Akt/mTorc1 pathway with a decrease in AMPA and NMDA receptor subunits and in synaptic currents. Akt2 injection in postsynaptic neurons is sufficient to reverse changes in synaptic currents generated by Auts2 haploinsufficiency. Using chromosome engineering based on targeted meiotic recombination, we generated two mouse models with Auts2 locus deletion and duplication. Deleted Auts2 locus mice display stereotypies (rearing), perseveration and abnormal recognition memory. Duplicated Auts2 locus mice display similar perseveration and abnormal recognition memory but also a decrease in cued and contextual fear memory. Gene dosage induce changes in brain sub-region neuronal networks. In the thalamo-lateral amygdala pathway linked to cued fear memory, we found synaptic impairments linked to AMPA receptors, with a specific decrease in pAKT/total AKT ratio in duplicated Auts2 mice. Altogether, our study thereby provides a novel mechanistic and potentially therapeutic understanding of synaptic AKT/mTORC1 deregulated signaling and its related behavioral and cognitive phenotypes.

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

“…We recently demonstrated that AUTS2 directly interacts with TTC3 a E3 ligase of AKT that regulates dendritic spine function via mTORC1-dependent local translation 45 (Fig. 6E).…”

“…The third type of Auts2 mouse model developed by our group 45 is based on either deletion or duplication of the ~1.2 Mb Auts2 locus. We evidenced repetitive and restricted behaviors (rearing) in Del/+ mice.…”