Reduction of BDNF levels in mutant htt mice produces neuronal loss in the striatum. A, Representative sections of DARPP-32 immunohistochemistry on wt mice (bdnf^+/+ htt^wt), R6/1 mice (bdnf^+/+ htt^m), bdnf heterozygous mice (bdnf^{+/ -} htt^wt), and bDM (bdnf^{+/ -} htt^m). B, C, We used DARPP-32 immunostaining to measure the volume of the cerebral cortex (B) and the striatum (C). B, The cerebral cortex shows the same atrophy in both genotypes with mutant htt. C, In contrast, the striatal volume is significantly lower in bDM with respect to R6/1 mice, indicating that the insufficient levels of this neurotrophin produce more severe striatal degeneration. D, E, At 30 weeks, bDM have striatal neuronal loss, counted by neuronal morphology in cresyl violet staining (D) or by NeuN immunohistochemistry (E). No decrease in neurons was detected in other genotypes. F, G, In n3DM (nt-3^+/- htt^m), the effects observed result from the addition of striatal and cortical reduction observed in individual genotypes, mutant htt and nt-3^+/-. H, I, No differences in cell loss were observed between nt-3 heterozygous with or without mutant htt. Both genotypes (nt-3^+/- htt^wt and nt-3^+/- htt^m) present a ∼25% reduction. ^*p < 0.05, ^**p < 0.005, and ^***p < 0.001 compared with wt mice (bdnf^+/+ htt^wt or nt-3^+/+ htt^wt); ⁺p < 0.05 and ⁺⁺⁺p < 0.001 compared with bdnf^+/+ htt^m or nt-3^+/+ htt^m mice; ^#p < 0.05, ^##p < 0.005, and ^###p < 0.001 compared with bdnf or nt-3 heterozygous mice, respectively.