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 the result of 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.
Highlights
Intellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting 1% of the global population [1,2]
We found that a mouse model of Bardet-Biedl Syndrome (BBS) (Bbs1M390R/M390R mice) has learning and memory defects
These BBS mouse models have difficulty associating an environment with a painful stimulus, a task designed to test context fear memory
Summary
Intellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting 1% of the global population [1,2]. I.e. ciliopathies, frequently present with ID, suggesting that cilia play an important role in learning and memory, yet the mechanisms underlying the phenotype remain unknown [7]. We reasoned that studying genetic ciliopathy mouse models can provide insights into the role of cilia in learning and memory. To this end, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS), which presents clinically with intellectual disability [8] in order to investigate the role of cilia in learning and memory. Clinical features of BBS include rod-cone dystrophy progressing to blindness, postaxial polydactyly, obesity, renal anomalies, and intellectual disability [10].
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