Hsu, Y. | bioRxiv Science

bioRxiv2022

Knockout of Bbs10 results in lack of cone electrical function and progressive retinal degeneration of rods and cones

Bardet Biedl Syndrome (BBS) is an autosomal recessive disorder caused by mutations in at least 22 different genes. A constant feature is early onset retinal degeneration leading to blindness, with variable central obesity, polydactyly, renal failure, and developmental anomalies. BBS type 10 (BBS10) is a common form caused by mutations in the BBS10 gene encoding a chaperonin-like protein. There are currently no treatments for the progressive vision loss. To aid in treatment development, a BBS10 mouse model was developed by knocking out the Bbs10 gene. Using optical coherence tomography (OCT), electroretinography (ERG), and a visually guided swim assay (VGSA), we demonstrate that Bbs10-/- mice have progressive retinal degeneration. Cone electrical function was absent although cones were anatomically present on histology and retained partial function based on VGSA. The retinal outer nuclear layer (photoreceptor nuclei) progressively thinned as demonstrated on OCT and histology, and rod electrical activity decreased over time on ERG. These phenotypes are more rapidly progressive than retinal degeneration in the Bbs1M390R/M390R knock-in mouse. They are consistent with a cone-rod dystrophy distinct from typical rod-cone degeneration in retinitis pigmentosa and recapitulate aspects of retinal degeneration observed in humans with BBS10. This study has implications for BBS10 gene therapy.

genetics↗

bioRxiv2020

A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment

Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are linked to impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning. Author summaryThe primary cilium is a microtubule-based membranous projection on the cell that is involved in multiple physiological functions. Patients who have cilia dysfunction commonly have intellectual disability. However, it is not known how cilia affect learning and memory. Studying mouse models of a cilia-based intellectual disability can provide insight into learning and memory. One such cilia-based intellectual disability is Bardet-Biedl Syndrome (BBS), which is caused by homozygous and compound heterozygous mutations of BBS genes. We found that a mouse model of BBS (Bbs1M390R/M390R mice) has learning and memory defects. In addition, we found that other mouse models of BBS have similar learning and memory defects. These BBS mouse models have difficulty associating an environment with an aversive stimulus, a task designed to test context fear memory. This type of memory involves the hippocampus. We found that Bbs1M390R/M390R mice have decreased cell production in the hippocampus. Treating Bbs1M390R/M390R mice with a compound (lithium) that increases cell production in the hippocampus improved the learning and memory deficits. Our results demonstrate a potential role for cilia in learning and memory, and indicate that lithium is a potential treatment, requiring further study, for the intellectual disability phenotype of BBS.

animal behavior and cognition↗