Hippocampal and Cortical Primary Cilia Are Required for Aversive Memory in Mice

Abstract

It has been known for decades that neurons throughout the brain possess solitary, immotile, microtubule based appendages called primary cilia. Only recently have studies tried to address the functions of these cilia and our current understanding remains poor. To determine if neuronal cilia have a role in behavior we specifically disrupted ciliogenesis in the cortex and hippocampus of mice through conditional deletion of the Intraflagellar Transport 88 (Ift88) gene. The effects on learning and memory were analyzed using both Morris Water Maze and fear conditioning paradigms. In comparison to wild type controls, cilia mutants displayed deficits in aversive learning and memory and novel object recognition. Furthermore, hippocampal neurons from mutants displayed an altered paired-pulse response, suggesting that loss of IFT88 can alter synaptic properties. A variety of other behavioral tests showed no significant differences between conditional cilia mutants and controls. This type of conditional allele approach could be used to distinguish which behavioral features of ciliopathies arise due to defects in neural development and which result from altered cell physiology. Ultimately, this could lead to an improved understanding of the basis for the cognitive deficits associated with human cilia disorders such as Bardet-Biedl syndrome, and possibly more common ailments including depression and schizophrenia.

Exploration of the cognitive, adaptive and behavioral functioning of patients affected with Bardet–Biedl syndrome

“…The recent identification of BBS genes as risk factors for ASD and the heightened incidence of patients with ASD symptoms in our sample of BBS patients, warrant further studies on the relationship between autism and BBS. Although the brain imaging studies of BBS patients are incomplete, data available from humans and the bbs animal models identified changes that may cause learning, behavior, and memory deficits (32)(33)(34)(35). Future studies on the association of brain imagining changes and neuropsychological functioning should provide valuable information.…”

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

“…A hypomorphic allele of Ift88 in the mouse, Tg737 orpk (Pazour et al, 2000) causes cystic kidneys and other phenotypes reminiscent of human ciliopathies (Reiter and Leroux, 2017). In the brain, IFT88 is important for cilia structure in the hippocampus and cortex, and when knocked out in these specific neuron populations results in memory deficits (Berbari et al, 2014). Additionally, Ift88 null mutants exhibit nearly identical embryonic phenotypes to those of Ttbk2 null mutants (Murcia et al, 2000).…”

G-Protein-Coupled Receptor Signaling in Cilia

“…Seminal studies using mouse knockout models have provided compelling evidence for cilia-dependent GPCR signaling in the brain. For example, mice lacking cilia on specific neuronal subpopulations in the brain manifest prominent phenotypes, such as obesity and learning and memory deficits (Davenport et al 2007;Berbari et al 2013Berbari et al , 2014. Moreover, mice lacking ciliary GPCRs or ciliary-enriched downstream effectors of GPCR signaling display similar phenotypes (Wang et al 2009(Wang et al , 2011Einstein et al 2010).…”