Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α

• Published in: Cell reports (Cambridge) Vol. 43; no. 4; p. 114056
• Main Authors: Molinaro, Gemma, Bowles, Jacob E., Croom, Katilynne, Gonzalez, Darya, Mirjafary, Saba, Birnbaum, Shari G., Razak, Khaleel A., Gibson, Jay R., Huber, Kimberly M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-04-2024; Elsevier
• Subjects: autism; cell size; circuit excitability; CP: Cell biology; CP: Neuroscience; ERα; mGluR5; protein synthesis; PTEN; signal transduction; somatosensory cortex; UP state; UP state; circuit excitability; CP: Cell biology; ERα; signal transduction; CP: Neuroscience; PTEN; protein synthesis; somatosensory cortex; mGluR5; cell size; autism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114056

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 (NSEPten 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 α (ERα) 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-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten 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.
[Display omitted]
•Sex and a high-confidence ASD-risk gene, Pten, interact to affect brain function and behavior•Deletion of Pten causes robust hyperexcitability of neocortical circuits in female mice•Circuit hyperexcitability is driven by mGluR5 and ERα signaling to ERK and protein synthesis•Female Pten KO neurons have enhanced mGluR5 and ERα-dependent protein synthesis
Molinaro et al. report enhanced cortical circuit excitability, selectively in females, in mouse models of Pten deletion. Hyperexcitability is driven by mGluR5 and ERα signaling to ERK and protein synthesis. Enhanced mGluR5-ERα interactions and enhanced mGluR5-dependent protein synthesis in Pten KO neurons may drive female-specific circuit effects.