Mice with pR927Q and pI712M Erbb4 Mutations Develop Features of Frontotemporal Dementia and ALS

Topic: Brain proteins, microglia and lab models

Barnes Maze Acquisition was performed on males (N = 4-5/genotype) after habituation and several days training. Heatmaps of grouped averages for acquisition day 5 show that ErbB4-R927Q mutants (homozygotes > heterozygotes) take longer finding the goal box, suggesting a gene dosage-dependent defect in spatial learning. CatWalk-XT was performed on Erbb4-R927Q mutant females (N = 4-6/genotype), with six complaint post-training walks/animal. Significantly lower mean intensities of the most intense paw prints occurred in the hindlimbs of mutants (Tukey's 2-way ANOVA). Multiple gene-dosage-dependent trends in altered gait metrics occurred, including footfall patterns, 2D/3D mean/max intensities, footfall sequence, print positions, standing and diagonal mean phase dispersions. DXA scans on Erbb4-R927Q mutant and wild-type males (N = 5-9 per genotype) showed decreased body weights and fat percentages in homozygotes. Whole body and limb regions of interest showed decreases in bone mineral density and content that was greater in homozygotes than in heterozygotes. Initial findings suggest gene dosage-dependent abnormalities in Erbb4-R927Q mutants that have features of FTLD and ALS. A wider battery of tests on more animals, at different ages and including the Erbb4-I712M mutants are underway. Neuropathology is being assessed following consensus recommendations for FTLD and ALS. Stereology/morphometry and other methods will assess loss of ErbB4-expressing inhibitory interneurons and synaptic loss and how this evolves temporally.

@article{spyropoulos2025-41445252,
  author  = {Spyropoulos, Demetri D. and Jenkins, Dorea P. and Carroll, Steven Lewis},
  title   = {{Mice with pR927Q and pI712M Erbb4 Mutations Develop Features of Frontotemporal Dementia and ALS}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70855_106736},
  pmid    = {41445252},
  url     = {https://doi.org/10.1002/alz70855_106736}
}

Key findings

• Barnes Maze Acquisition was performed on males (N = 4-5/genotype) after habituation and several days training.
• Heatmaps of grouped averages for acquisition day 5 show that ErbB4-R927Q mutants (homozygotes > heterozygotes) take longer finding the goal box, suggesting a gene dosage-dependent defect in spatial learning.
• CatWalk-XT was performed on Erbb4-R927Q mutant females (N = 4-6/genotype), with six complaint post-training walks/animal.
• Significantly lower mean intensities of the most intense paw prints occurred in the hindlimbs of mutants (Tukey's 2-way ANOVA).
• Multiple gene-dosage-dependent trends in altered gait metrics occurred, including footfall patterns, 2D/3D mean/max intensities, footfall sequence, print positions, standing and diagonal mean phase dispersions.

Why it matters

Mice carrying Erbb4 mutations showed gene dosage-dependent problems with spatial learning, gait, body weight, and bone density that resemble features of frontotemporal dementia and ALS. These are early findings in small numbers of animals, and more testing is underway, so no treatment or prevention is established.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70855_106736
• PubMed: 41445252
• Original source →
• Free full text: Alzheimer s & Dementia →

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