Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α
Gemma Molinaro,
Jacob E. Bowles,
Katilynne Croom,
Darya Gonzalez,
Saba Mirjafary,
Shari G. Birnbaum,
Khaleel A. Razak,
Jay R. Gibson,
Kimberly M. Huber
Affiliations
Gemma Molinaro
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Jacob E. Bowles
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Katilynne Croom
Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA
Darya Gonzalez
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Saba Mirjafary
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Shari G. Birnbaum
Department of Psychiatry, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Khaleel A. Razak
Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA; Department of Psychology, University of California, Riverside, Riverside, CA, USA
Jay R. Gibson
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
Kimberly M. Huber
Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA; Corresponding author
Summary: 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.
