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

doi:10.1016/j.celrep.2024.114056

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

Cell Rep. 2024 Apr 23;43(4):114056. doi: 10.1016/j.celrep.2024.114056. Epub 2024 Apr 5.

Authors

Gemma Molinaro¹, Jacob E Bowles¹, Katilynne Croom², Darya Gonzalez¹, Saba Mirjafary¹, Shari G Birnbaum³, Khaleel A Razak⁴, Jay R Gibson¹, Kimberly M Huber⁵

Affiliations

¹ Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
² Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA.
³ Department of Psychiatry, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
⁴ Graduate Neuroscience Program, University of California, Riverside, Riverside, CA, USA; Department of Psychology, University of California, Riverside, Riverside, CA, USA.
⁵ Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: kimberly.huber@utsouthwestern.edu.

PMID: 38581678
DOI: 10.1016/j.celrep.2024.114056

Abstract

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.

Keywords: CP: Cell biology; CP: Neuroscience; ERα; PTEN; UP state; autism; cell size; circuit excitability; mGluR5; protein synthesis; signal transduction; somatosensory cortex.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autistic Disorder* / genetics
Autistic Disorder* / metabolism
Autistic Disorder* / pathology
Autistic Disorder* / physiopathology
Disease Models, Animal*
Estrogen Receptor alpha* / metabolism
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
Neocortex* / metabolism
Neocortex* / pathology
PTEN Phosphohydrolase* / genetics
PTEN Phosphohydrolase* / metabolism
Pyramidal Cells / metabolism
Receptor, Metabotropic Glutamate 5* / metabolism
Social Behavior

Substances

Estrogen Receptor alpha
Grm5 protein, mouse
PTEN Phosphohydrolase
Pten protein, mouse
Receptor, Metabotropic Glutamate 5
Esr1 protein, mouse

Grants and funding

U54 HD104461/HD/NICHD NIH HHS/United States