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Primary cilia have well characterized roles in early brain development, relaying signals critical for neurogenesis and brain formation during embryonic stages. Less understood are the contributions of cilia-mediated signaling to postnatal brain function. Several cilia-localized receptors that bind neuropeptides and neurotransmitters endogenous to the brain have been identified in adult neurons, but the functional significance of signaling through these cilia-localized receptors is largely unexplored. Ciliopathic disorders in humans often manifest with neurodevelopmental abnormalities and cognitive deficits. Intriguingly, recent research has also linked several neuropsychiatric disorders and neurodegenerative diseases to ciliary dysfunction. This review summarizes recent evidence suggesting that cilia signaling may dynamically regulate postnatal neuronal physiology and connectivity, and highlights possible links among cilia, neuronal circuitry, neuron survival, and neurological disorders.

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.

The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies.