| First Author | Hooshmandi M | Year | 2023 |
| Journal | Neuron | Volume | 111 |
| Issue | 19 | Pages | 3028-3040.e6 |
| PubMed ID | 37473758 | Mgi Jnum | J:366421 |
| Mgi Id | MGI:7781939 | Doi | 10.1016/j.neuron.2023.06.017 |
| Citation | Hooshmandi M, et al. (2023) Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome. Neuron 111(19):3028-3040.e6 |
| abstractText | Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2alpha phosphorylation (p-eIF2alpha), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1(-/y)). We further show that the decrease in p-eIF2alpha is mediated via activation of mTORC1. Genetic reduction of p-eIF2alpha only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1(-/y) mice, restoration of p-eIF2alpha solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS. |
