Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α
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 selectiv...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472400384X |
| _version_ | 1827292122309459968 |
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| author | Gemma Molinaro Jacob E. Bowles Katilynne Croom Darya Gonzalez Saba Mirjafary Shari G. Birnbaum Khaleel A. Razak Jay R. Gibson Kimberly M. Huber |
| author_facet | Gemma Molinaro Jacob E. Bowles Katilynne Croom Darya Gonzalez Saba Mirjafary Shari G. Birnbaum Khaleel A. Razak Jay R. Gibson Kimberly M. Huber |
| author_sort | Gemma Molinaro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T12:51:11Z |
| format | Article |
| id | doaj.art-7c73a4c9eb664f3cb970e1280a5f33cf |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-24T12:51:11Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7c73a4c9eb664f3cb970e1280a5f33cf2024-04-06T04:39:51ZengElsevierCell Reports2211-12472024-04-01434114056Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor αGemma Molinaro0Jacob E. Bowles1Katilynne Croom2Darya Gonzalez3Saba Mirjafary4Shari G. Birnbaum5Khaleel A. Razak6Jay R. Gibson7Kimberly M. Huber8Department of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USADepartment of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USAGraduate Neuroscience Program, University of California, Riverside, Riverside, CA, USADepartment of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USADepartment of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USADepartment of Psychiatry, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USAGraduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA; Department of Psychology, University of California, Riverside, Riverside, CA, USADepartment of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USADepartment of Neuroscience, O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472400384XCP: NeuroscienceCP: Cell biology |
| spellingShingle | Gemma Molinaro Jacob E. Bowles Katilynne Croom Darya Gonzalez Saba Mirjafary Shari G. Birnbaum Khaleel A. Razak Jay R. Gibson Kimberly M. Huber Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α Cell Reports CP: Neuroscience CP: Cell biology |
| title | Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α |
| title_full | Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α |
| title_fullStr | Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α |
| title_full_unstemmed | Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α |
| title_short | Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α |
| title_sort | female specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mglur5 and estrogen receptor α |
| topic | CP: Neuroscience CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S221112472400384X |
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