Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD) are characterized by progressive neurodegeneration affecting behavior and executive function.
• FTLD-TDP, often co-occurring with amyotrophic lateral sclerosis (ALS), involves TDP43 inclusions.
• Autosomal dominant mutations in the ERBB4 gene have been linked to familial FTD/ALS or ALS, with observed reduced ERBB4 activity.

Purpose of the Study:

• To investigate the neuropathology associated with ERBB4 mutations.
• To generate and analyze mouse models carrying familial ERBB4 mutations (p.I712M and p.R927Q).
• To assess behavioral, gait, and body composition changes in Erbb4 mutant mice.

Main Methods:

• Generation of Erbb4 heterozygous and homozygous mutant mice (p.I712M and p.R927Q).
• Behavioral testing using the Barnes Maze for spatial learning.
• Gait and mobility analysis with CatWalk-XT.
• Body composition analysis via DXA scans.

Main Results:

• Erbb4-R927Q mutants exhibited gene dosage-dependent defects in spatial learning (Barnes Maze).
• Mutant mice showed altered gait metrics, including hindlimb paw print intensities and footfall patterns.
• Decreased body weight, fat percentage, bone mineral density, and content were observed in homozygotes.

Conclusions:

• Initial findings indicate gene dosage-dependent abnormalities in Erbb4-R927Q mutants, presenting features relevant to FTD and ALS.
• Further studies involving a wider range of tests, more animals, and the Erbb4-I712M mutation are ongoing.
• Neuropathological assessments are underway to evaluate the loss of ErbB4-expressing interneurons and synaptic integrity.