Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• NMDA receptor (NMDAR) dysfunction is implicated in encephalopathies linked to mutations in NMDAR subunit genes (GRIN1, GRIN2A, GRIN2B).
• These mutations result in intellectual disability, autism, epilepsy, and motor dysfunction.

Purpose of the Study:

• To investigate if Grin1 loss-of-function variants cause detectable MRI structural brain changes.
• To examine the developmental progression of these structural changes in relation to cognitive impairments.

Main Methods:

• Magnetic resonance imaging (MRI) was performed on male Grin1-/- knockdown (GluN1KD) mice at three, six, and twelve weeks of age.
• Deformation-based morphometry analyzed neuroanatomical differences.
• FluoroJade immunofluorescence identified degenerating neurons.

Main Results:

• Volumetric reductions in the substantia nigra and striatum were observed in GluN1KD mice across all ages.
• Limbic structure changes appeared at six weeks; white matter deficits began at three weeks and worsened over time.
• Degenerating neurons were present in twelve-week-old GluN1KD mice.

Conclusions:

• Grin1 loss-of-function mutations lead to early volume reductions in dopaminergic brain structures.
• Limbic and white matter changes manifest later and are more severe in mature mice.
• Evidence of neuronal degeneration suggests ongoing cell loss due to NMDAR hypofunction.