Negr1 upregulation converges into core impaired processes in autism spectrum disorders: from pathophysiology to potential therapeutic target

Autism spectrum disorders (ASDs) are a group of medical conditions encompassing diverse neurodevelopmental syndromes (e.g., Fragile X) caused by alterations in specific genes. Although all ASDs converge into common core behaviors (i.e. social deficits and repetitive behaviors), genetic variants in ASD are very heterogeneous. Nowadays there is no effective treatment for core behavior impairments in autism, and numerous key mechanisms remain unknown, although preliminary insights have been gained. Here, we describe a cleavable cell-adhesion molecule (Negr1) as upregulated in the brain of 5 diverse mouse models of ASDs (including Fragile X) and postmortem brains from people with autism or Fragile X, and causative of core ASD behaviors and brain alterations when up-regulated in wild-type (WT) animals in vivo. In particular, we found that Negr1 upregulation in the prefrontal cortex of WT mice was sufficient to induce disruptions in sociability, repetitive behaviors and brain anatomy. Moreover, we found that Negr1 is excessively cleaved in the Fragile X mouse model and we demonstrated that the soluble form of Negr1 is sufficient and necessary to cause social deficits in mice. We also found AKT activation as a downstream effector of Negr1. Altogether, our results on the causal link between Negr1 upregulation and ASD core features in WT mice, together with our findings on Negr1 dysregulation in diverse ASD mouse models, may explain how a wide variety of ASD genetic variants converge into a unique core group of impaired processes during brain development. Our results also indicate regulation of Negr1 and its pathway as a possible target for future therapies.