Neural SMG7 deficiency induces autism-like behaviours via PKD1 upregulation.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. Emerging evidence links several autism susceptibility genes to the nonsense-mediated decay (NMD) pathway, which maintains the homeostasis of gene transcription and protein translation in the nervous system. However, the role of Suppressor with morphogenetic effect on genitalia 7 (Smg7), an essential NMD factor, in brain function and ASD remains largely unknown. Here, we generated an Emx1-Cre-mediated conditional Smg7 knockout (Smg7cko) mouse model to investigate its neurological consequences. We found that both male and female Smg7cko mice exhibited autism-like behaviors, including impaired social interaction and communication, repetitive behaviors, anxiety-like traits, and learning and memory deficits. These phenotypes were accompanied by neuronal hyperexcitability and increased dendritic spine density in layer II/III pyramidal neurons of the hippocampus and the medial prefrontal cortex (mPFC). Notably, Smg7 deletion led to pronounced upregulation of Protein Kinase D1 (PKD1) transcripts, an NMD target, in these brain regions. Strikingly, adeno-associated virus (AAV)-mediated PKD1 knockdown (AAVsh-PKD1) in the hippocampus and mPFC significantly rescued social deficits in Smg7-deficient mice. Together, these findings identify Smg7 as a key regulator of neuronal function and behavior, and reveal PKD1 upregulation as a pathogenic mechanism underlying ASD-like phenotypes, providing new insight into NMD deficiency in ASD pathophysiology and a potential therapeutic target.