Abstract
Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.
Highlights
Dendritic spines are small protrusions that cover the dendrites of most principal neurons in the vertebrate central nervous system (CNS), where they typically serve as the postsynaptic part of excitatory synapses [1]
Given that primary cilia are required for the formation of neuronal dendrites [21], we investigated the effect of loss of ciliary Bbs proteins on the dendritic morphology of principal neurons of Bbs mouse models
We found that the total spine density was reduced by 55% in dentate granule (DG) granule cells of P42 old Bardet-Biedl syndrome 4 (Bbs4)−/− mice (Fig 1A and 1B and S1 Video)
Summary
Dendritic spines are small protrusions that cover the dendrites of most principal neurons in the vertebrate central nervous system (CNS), where they typically serve as the postsynaptic part of excitatory synapses [1]. Funded by National Institute for Health Research (GOS ICH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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