Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder affecting a range of cellular and molecular functions in the brain. Deficits in adult hippocampal neurogenesis (AHN) have been documented in the R6/1 mouse model of HD. Here we examined basal and running-induced neuronal precursor proliferation in adult female and male R6/1 HD mice. We further tested whether sequential delivery of voluntary running followed by environmental enrichment could synergistically enhance functional AHN in female R6/1 HD mice. R6/1 HD mice engaged in significantly reduced levels of voluntary running, with males showing a more severe deficit. Basal neural precursor proliferation in the hippocampal sub-granular zone remained unchanged between female and male R6/1 HD mice and neither sex significantly responded to running-induced proliferation. While discrete provision of running wheels and enriched environments doubled AHN in adult female R6/1 HD mice it did not reflect the significant 3-fold increase in female wildtypes. Nevertheless, triple-label c-Fos/BrdU/NeuN immunofluorescence and confocal microscopy provided evidence that the doubling of AHN in female R6/1 HD mice was functional. Intrinsic cellular dysfunction mediated by protein aggregates containing mutant huntingtin (mHtt) did not appear to coincide with AHN deficits. In the hippocampus of female R6/1 HD mice, proliferating precursors and 6 week old adult-generated neurons were devoid of mHtt immuno-reactive aggregates, as were endothelial, microglial and astroglial cells populating the neurogenic niche. Serum transforming growth factor-β concentrations remained unaltered in female R6/1 HD mice as did the hippocampal levels of proliferating microglia and glial fibrillarly acidic protein expression. Examining the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis showed no change in base-line serum GH between genotypes. However, despite a reduced distance, acute running increases serum GH in both female wildtype and R6/1 HD mice. Serum IGF-1 levels were increased in female R6/1 HD mice compared to wildtypes during daytime inactive period, while hippocampal levels of the IGF-1 receptor remained unchanged. Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Total Akt levels were decreased in the hippocampus of both control and running R6/1 HD mice. Our results show adult-generated hippocampal neurons in female R6/1 HD mice express c-Fos and that running and Akt signaling deficits may mediate reduced basal and running-induced AHN levels.