Ectopic expression of BBS1 rescues male infertility, but not retinal degeneration, in a BBS1 mouse model.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy for which there are no current effective treatments. BBS is a genetically heterogeneous disease, though the M390R mutation in BBS1 is involved in ~25% of all genetic diagnoses of BBS. The principle features of BBS include retinal degeneration, obesity, male infertility, polydactyly, intellectual disability, and renal abnormalities. Patients with mutations in BBS genes often present with night blindness within the first decade of life, which progresses to complete blindness. This is due to progressive loss of photoreceptor cells. Male infertility is caused by a lack of spermatozoa flagella, rendering them immobile. In this study, we have crossed the wild-type human BBS1 gene, driven by the CAG promoter, onto the Bbs1M390R/M390R mouse model to determine if ectopic expression of BBS1 rescues male infertility and retinal degeneration. qRT-PCR indicates that the BBS1 transgene is expressed in multiple tissues throughout the mouse, with the highest expression seen in the testes, and much lower expression in the eye and hypothalamus. Immunohistochemistry of the transgene in the eye showed little if any expression in the photoreceptor outer nuclear layer. When male Bbs1M30R/M390R;BBS1TG+ mice are housed with WT females, they are able to sire offspring, indicating that the male infertility phenotype of BBS is rescued by the transgene. Using electroretinography (ERGs) to measure retinal function and optical coherence tomography to measure retinal thickness, we show that the transgene does not confer protection against retinal degeneration in Bbs1M300R/M390R;BBS1TG+ mice. The results of this study indicate that the male infertility aspect of BBS is an attractive target for gene therapy.

Effects of age and social isolation on murine hippocampal biochemistry and behavior.

Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone (CORT) and interleukin-6 (IL-6) were determined and serum collected for basal CORT analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum CORT determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum CORT post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum CORT post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA:5-HT). In conclusion, the lack of response to SI in the aged mice may affect health by preventing them adapting to new stressors, while the synergistic effects of SI with age would increase allostatic load and enhance the deleterious effects of the ageing process.