Activity-Dependent Differential Regulation of Auts2 Isoforms In Vitro and In Vivo

Autism spectrum disorder (ASD) is a neurodevelopmental disorder of unknown cause, although one hypothesis suggests a potential imbalance between excitation and inhibition that leads to changes in neuronal activity and a disturbance in the brain network. However, the mechanisms through which neuronal activity contributes to the development of ASD remain largely unexplained. In this study, we described that neuronal activity at the transcriptional and translational levels regulated the expression of Auts2 isoforms. The prolonged stimulation of cultured cortical neurons significantly reduced the auts2 transcripts, accompanied by the decrease of FL-Auts2 protein, as well as one of the short isoforms (S-Auts2 var.1). Blocking neuronal activity increased the number of auts2 transcripts but not protein levels. Furthermore, blocking the NMDA receptors during stimulation could partially restore the FL-Auts2 and S-Auts2 var.1 at protein level, but not at mRNA level. Finally, Auts2 expression in the hippocampus was reduced in mice exposed to an enriched environment, a behavior paradigm designed to increase the brain activity through abundant sensory and social stimulations. Thus, our study revealed a novel regulatory effect of neuronal activity on the transcription and translation of ASD-risk gene auts2.