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

Area of Science:

• Neuroscience
• Genetics

Background:

• Sensory abnormalities affect ~90% of individuals with autism spectrum disorders (ASD), but their mechanisms are poorly understood.
• The NMDA receptor subunit GluN2B is implicated in ASD, yet its role in sensory dysfunction is unclear.

Purpose of the Study:

• To investigate if GRIN2B mutations cause sensory abnormalities and altered brain connectivity in autism spectrum disorders (ASD).
• To explore the role of the anterior cingulate cortex (ACC) in mediating these effects.

Main Methods:

• Utilized Grin2b-mutant mice, including those with a patient-derived C456Y mutation.
• Assessed sensory hypersensitivity using mechanical, thermal, and electrical stimuli.
• Employed c-fos and functional magnetic resonance imaging (fMRI) to analyze brain activity and connectivity, focusing on the ACC.
• Investigated synaptic transmission in ACC pyramidal neurons.
• Used chemogenetics to inhibit ACC pyramidal neurons.

Main Results:

• Grin2b-mutant mice exhibited behavioral sensory hypersensitivity and brain hyperconnectivity, centered on the ACC.
• The ACC showed hyperactivity and increased connectivity with other brain regions.
• ACC pyramidal neurons displayed enhanced excitatory synaptic transmission.
• Inhibition of ACC pyramidal neurons normalized ACC hyperconnectivity and sensory hypersensitivity.

Conclusions:

• GluN2B plays a critical role in regulating cortical connectivity and sensory processing in the context of autism spectrum disorders (ASD).
• The anterior cingulate cortex (ACC) is a key region involved in mediating sensory abnormalities associated with GRIN2B mutations.