Basic Science and Pathogenesis

Frontotemporal dementia (FTD) involves progressive deterioration of behavior, executive function, personality/traits and is evident structurally as frontotemporal lobar degeneration (FTLD). FTLD with pathological TDP43 neural/glial inclusions (FTLD-TDP), often coexists with TDP43-positive amyotrophic lateral sclerosis (ALS). Several families have been identified that inherit autosomal dominant FTLD/ALS or ALS alone and mutations in the gene encoding the ERBB4 receptor tyrosine kinase (RTK). Although the neuropathology associated with ERBB4 mutations remains obscure, ERBB4 with p.R927Q or p.I712M mutations show reduced phosphorylation when stimulated with the ERBB4 ligand neuregulin-1β, suggesting that reduced ERBB4 activity causes FTLD/ALS or ALS.

We generated mice carrying p.I712M (familial FTLD/ALS) or p.R927Q (familial ALS only) Erbb4 mutations. We performed initial studies of behavior (Barnes Maze), gait-mobility (Catwalk-XT) and body composition (DXA scans) on Erbb4 heterozygous and homozygous mutants and wild-type littermates.

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.