Anterior cingulate cortex-related functional hyperconnectivity underlies sensory hypersensitivity in Grin2b-mutant mice

Mol Psychiatry. 2024 Oct;29(10):3195-3207. doi: 10.1038/s41380-024-02572-y. Epub 2024 May 4.

Abstract

Sensory abnormalities are observed in ~90% of individuals with autism spectrum disorders (ASD), but the underlying mechanisms are poorly understood. GluN2B, an NMDA receptor subunit that regulates long-term depression and circuit refinement during brain development, has been strongly implicated in ASD, but whether GRIN2B mutations lead to sensory abnormalities remains unclear. Here, we report that Grin2b-mutant mice show behavioral sensory hypersensitivity and brain hyperconnectivity associated with the anterior cingulate cortex (ACC). Grin2b-mutant mice with a patient-derived C456Y mutation (Grin2bC456Y/+) show sensory hypersensitivity to mechanical, thermal, and electrical stimuli through supraspinal mechanisms. c-fos and functional magnetic resonance imaging indicate that the ACC is hyperactive and hyperconnected with other brain regions under baseline and stimulation conditions. ACC pyramidal neurons show increased excitatory synaptic transmission. Chemogenetic inhibition of ACC pyramidal neurons normalizes ACC hyperconnectivity and sensory hypersensitivity. These results suggest that GluN2B critically regulates ASD-related cortical connectivity and sensory brain functions.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / physiopathology
  • Disease Models, Animal
  • Gyrus Cinguli* / physiopathology
  • Magnetic Resonance Imaging* / methods
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • Receptors, N-Methyl-D-Aspartate* / genetics
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Synaptic Transmission / physiology

Substances

  • Receptors, N-Methyl-D-Aspartate
  • NR2B NMDA receptor