Abstract
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 summary The 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Data Availability: All relevant data are within the paper and its Supporting Information files. Additional data that support the findings of this study are available from the corresponding author upon reasonable request.
Funding: This work was supported by NIH grants RO1 EY011298 and R01 EY017168 (to V.C.S.), and the Roy J. Carver Charitable Trust (V.C.S.). The work was also supported and greatly facilitated by the core facilities funded by NIH grant P30 EY025580 (PI: V.C.S.). AAP was supported by the Brockman Foundation, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, G.R. Lincoln Family Foundation, Wick Foundation, the Leonard Krieger Fund of the Cleveland Foundation, Gordon & Evie Safran, the Louis Stokes VA Medical Center resources and facilities, project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment, NIH-NIA RO1AG066707 and the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center (NIH/NIA: 1 P30 AGO62428-01).