| First Author | Molinaro G | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 4 | Pages | 114056 |
| PubMed ID | 38581678 | Mgi Jnum | J:348022 |
| Mgi Id | MGI:7627899 | Doi | 10.1016/j.celrep.2024.114056 |
| Citation | Molinaro G, et al. (2024) Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor alpha. Cell Rep 43(4):114056 |
| abstractText | Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons ((NSE)Pten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor alpha (ERalpha) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERalpha complexes are generally elevated in female cortices, and genetic reduction of ERalpha rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in (NSE)Pten KO females. Female (NSE)Pten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior. |
