Abstract
Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.
Highlights
Primary cilia are microtubule-based compartmentalized organelles that are present on most mammalian cell types including neurons (Gerdes et al, 2009; Louvi and Grove, 2011)
Neuronal morphology is unaffected upon acute disruption of ciliary signaling in the postnatal cortex Ciliogenesis in neocortical pyramidal neurons occurs progressively during early postnatal development, beginning at birth, with cilia reaching maximal lengths after several weeks (Arellano et al, 2012)
We show here that cilia play a critical role in the maintenance of neuronal excitability in the postnatal cortex
Summary
Primary cilia are microtubule-based compartmentalized organelles that are present on most mammalian cell types including neurons (Gerdes et al, 2009; Louvi and Grove, 2011). Similar to the localization patterns of these receptors, AC3 is enriched in the cilia of diverse neuron types in the brain (Berbari et al, 2007, Guadiana 2016; Bishop et al, 2007) Mutations in these receptors and AC3 are associated with a range of cognitive, metabolic, and behavioral disorders that are hallmarks of many ciliopathies (Chen et al, 2016; Einstein et al, 2010; Lee and Gleeson, 2011; Loktev and Jackson, 2013; Wang et al, 2011; Youn and Han, 2018). These receptors continue to be expressed in neuronal cilia in adults, and many of the cognate neurotransmitter and neuropeptide ligands are released locally by neurons or modulatory inputs, suggesting that cell-cell signaling through cilialocalized receptors plays an important role in the postnatal brain. Our results indicate that neuropeptidergic signaling via cilia-localized receptors dynamically modulates synaptic strength, and plays a critical role in regulating neuronal excitability in the postnatal mammalian brain
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
