The neuronal cilium – a highly diverse and dynamic organelle involved in sensory detection and neuromodulation

Cilia are fascinating organelles that act as cellular antennae, sensing the cellular environment. Cilia gained signi ﬁ cant attention in the late 1990s after their dysfunction was linked to genetic diseases known as ciliopathies. Since then, several breakthrough discoveries have uncovered the mechanisms underlying cilia bio-genesis and function. Like most cells in the animal kingdom, neurons also harbor cilia, which are enriched in neuromodulatory receptors. Yet, how neuronal cilia modulate neuronal physiology and animal behavior remains poorly understood. By comparing ciliary biology between the sensory and central nervous systems (CNS), we provide new perspectives on the functions of cilia in brain physiology.

they sense chemical cues [16,17].Olfactory cilia contain all the necessary machinery for chemosensation, including the odorant G protein-coupled receptors (GPCRs) and the channels triggering membrane depolarization [18].Ciliary function in the olfactory system is widely conserved from nematodes to mammals and necessary for olfaction [17,19,20].
In the retina, photoreceptors harbor a modified connecting cilium (Figure 1B) that connects the cell soma to the photosensory outer segments (OSs).The OSs contain membrane rafts enriched with rhodopsin, which, together with retinal cofactors, form a photopigment that initiates the phototransduction cascade [21].Since the connecting cilia of the photoreceptors are involved in transporting molecules from the cell soma to the OS, ciliary dysfunction leads to defects in protein trafficking and OS structural integrity, ultimately causing photoreceptor degeneration and blindness [21,22].
In the vertebrate inner ear, hair cell cilia are not directly involved in mechanosensing.Instead, cilia are essential for assembling the microvilli-based stereocilia, which detect mechanical vibrations through the tip links [23].Cilia are commonly involved in mechanosensing (Figure 1C) in various tissues and species [24] (e.g., the chordotonal organs in Drosophila [25], or in vertebrate hair cells during development when the stereocilia are not fully mature [26]).

Box 1. Primary ciliary dynamics in neuronal progenitors
Since the presence of cilia is incompatible with mitosis, primary cilia in cycling neuronal precursor cells are highly dynamic in terms of cilium assembly and disassembly.Progenitor cells assemble cilia when exiting mitosis and disassemble them at cell cycle re-entry, that is, disassembly starts at the G1-S transition and is completed at the G2-M transition [1].Cells utilize different ciliary disassembly pathways, which are discussed in detail in other reviews [1,121].This process is tightly controlled, as delayed ciliary disassembly hinders cells from mitotic entry.This is particularly important in neuronal progenitors because their abundance and diversity expand exponentially during development to generate brains with various neuronal populations [122,123].Accordingly, defects in the temporal kinetics of cilium disassembly disrupt progenitor cell diversity and severely impact brain development [10,11].
Since differentiated neurons do not re-enter cell cycle under physiological conditions, they usually do not fully disassemble their cilia.An exception to this rule are cerebellar granule cells, which undergo ciliary disassembly through mechanisms distinct from the ones in progenitors [73].In this context, future work should investigate the precise structural and molecular organization at the site where cilia emerge from the cell surface, such as the ciliary pocket and pit, since these have often been seen in dividing cells and are indicative of vesicular transport.Recent analyses of large electron microscopy datasets have shown that ciliary pockets are more frequently observed in proliferating progenitors than differentiated neurons [49,50], supporting a faster remodeling of cilia in progenitors than in post-mitotic neurons.

Box 2. Primary cilia-dependent Hedgehog signaling during brain development
Primary cilia serve as signaling hubs during neuronal development by transducing various signaling pathways, including Hedgehog, Notch, Wnt, GPCR-mediated, and PDGFRA-mediated signaling [1,2,124].Among these, canonical Hedgehog signaling is critical at the early stage of brain development in vertebrate neural tube patterning [1,125].Hedgehog ligands bind their ciliary receptor Patched 1 (PTCH1), which initiates the signaling cascade and, in turn, regulates gene expression [124,125].Notably, Hedgehog signaling components dynamically localize in and out of the cilium, depending on whether the signaling pathway is turned ON or OFF.In the OFF state, PTCH1 is located at the ciliary membrane, inhibiting the atypical GPCR Smoothened (SMO).Concomitantly, ciliary SMO levels are maintained at a low level due to its ubiquitination and removal from the cilium.Upon binding of the Hedgehog ligands, PTCH1 is inactivated and exits from the cilium.In turn, SMO accumulates in the cilium.Following its activation, SMO changes its confirmation, which blocks the phosphorylation of GLI2/3 by protein kinase A (PKA) and, thereby, activates GLI2/3, which traffic to the nucleus to drive the expression of Hedgehog target genes [1,124,125].
Since ciliary assembly and disassembly are dynamic processes, signaling events, including Hedgehog, should be in tight coherence with the ciliary dynamics.In other words, the relative amount of Hedgehog signal titrated and transduced in neuronal progenitors depends on the ciliary status.Thus, the cilia are dynamic, as well as their associated signaling.Increasing evidence shows that ciliary dynamics also impact Hedgehog signaling in differentiating and fully mature neurons [68,72,112,116].

Ciliary diversity in sensory systems
Cilia in sensory cell types are highly specialized to accomplish their distinct function (Figure 1).For example, olfactory cilia are surprisingly long, with more than 100 μm lengths in mice [27] and frogs [28].Olfactory cilia also display highly elaborated arborization, as seen in Caenorhabditis elegans [19,29], providing a larger membrane surface for enhanced detection of olfactory cues.For cilia-dependent mechanosensing, cilia bending is commonly detected through specialized structures within the cilia or at the apical part of the cell [25].For instance, microvilli located at the base of the sensory cilium and connected by tip-link-like fibers, similar to hair cells, have been described in mechanosensory cells; for example, in Platynereis and cnidarians [24,25,30] (Figure 1C).Alternatively, mechanosensory channels may be directly localized in the cilia.This is the case for chordotonal cells in Drosophila, where the mechanosensor NompC is enriched at the distal part of the cilia [31,32] (Figure 1C).
Besides exhibiting various morphologies, cilia in sensory systems may also display an altered axonemal ultrastructure.For instance, olfactory and mechanosensory cilia commonly harbor an extra pair of microtubules at their core, known as the central pair (referred to as 9+2 cilia) [17,30], which is the hallmark of motile cilia [33,34] and not commonly seen in primary cilia (referred to as a 9+0 cilia).However, the cilia of olfactory sensory neurons and inner ear hair cells are usually immotile, except in some amphibians, like Rana pipiens, which harbor motile cilia on their olfactory neurons [35].The central pair is suggested to provide the extra stability needed for their function [36].In other systems, including photoreceptors, the base of the cilium, including the transition zone, has undergone some specialization.In photoreceptors, the transition zone is exceptionally long, to support its role in protein trafficking from the cell soma to the OS [37].

Photoreceptor
Mechanosensing cells CNS neuron In chordotonal cells of the fruitfly, the mechanosensory channel NompC (red), which detects cilia bending, is expressed in the distal part of the cilium after the ciliary dilatation.Cilia in mechanosensory cells can have a 9+0 (chordotonal cells) or 9+2 (vertebrate hair cells) ultrastructure.(D) Cilia of central nervous system neurons have a 9+0 structure and usually emanate from the cell body.The structure of cnidarian hair cells is modified from [126], and chordotonal cells from [32].
In the sensory system, ciliary diversity is well described.However, the genetic programs and cellular mechanisms leading to the specialization of ciliary structure are only starting to be uncovered.For instance, ciliated cells can alter ciliogenesis pathways to generate cilia with diverse ultrastructure.This is the case for olfactory sensory neurons and hair cells, which express the master transcriptional regulator of motile ciliogenesis Foxj1, despite not having motile cilia [35,[38][39][40].These cells repurposed the Foxj1-dependent transcription program to generate cilia with motile cilia-like features [35].Divergent tubulin isotypes have been associated with ciliary specialization in C. elegans [41] and mammals [42].Given that cilia are highly diverse across species and cell types [24,[43][44][45][46][47], unraveling mechanisms underlying ciliary diversity throughout evolution could give new insights into the context-specific functions of cilia.

Cilia in CNS neurons are diverse and dynamic
Besides the sensory organs, cilia are found in nearly all types of neurons of the vertebrate CNS [48][49][50].Cilia were also described in some ganglionic neurons of cnidarians [51][52][53], in CNS neurons of the chordate Ciona intestinalis [54,55], but not in Drosophila and C. elegans [56,57], suggesting that some species have evolved to maintain neuronal cilia to perform specific physiological functions.Notably, Drosophila, in contrast to many other species, including all vertebrates and the last common ancestor of bilaterians, does not require cilia for transducing Hedgehog signaling, a key, cilia-dependent neurodevelopmental signaling pathway [43,46,57].

Diverse content of neuronal cilia
There is a diversity in the expression of markers among neuronal cilia.While most neuronal cilia express AC3 [61,64,65], HTR6 is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal, medium-sized spiny neurons, and in a minor population of interneurons [64].Similarly, SSTR3 is enriched in cortical excitatory neurons, with rare expression (<10%) in the interneurons [66].In addition, the expression of cilia markers is not uniform during the life cycle of neurons.While AC3 expression in the CA1 region of the hippocampus remains relatively stable after postnatal day 10 (P10), ARL13B reaches high levels in the stratum pyramidal layer at P10 before fading away at P40 in mice [67].
Ciliary length, ultrastructure, and orientation are dynamic in space and time Recent studies aimed to gain further insights on the abundance, structure, length, orientation, and dynamics of cilia in the CNS.Ciliogenesis is tightly connected to the cell cycle and occurs following cell division during neuronal differentiation [1,2] (Box 1).Ciliary length increases during postnatal development in the mouse dorsal cortex over several weeks to reach stabilized lengths at P60 [48].For fully differentiated neurons, ciliary length can range from only a few micrometers up to 20 μm, depending on the species, brain region, and cell type [49,50,64,[68][69][70][71].One exception is cerebellar granule cells, which are devoid of cilia [72,73].
Recent studies using volumetric electron microscopy in the human anterior temporal lobe cortex [49] and mouse primary visual cortex [50] reported that almost all excitatory and inhibitory neurons (>99.5%)harbor cilia.Ciliary pockets, which are indicative of vesicle transport and often seen in dividing cells, such as retinal pigmented epithelial cells and neural progenitor cells [10,74], were observed in 24-56% of neurons in the human cortex [49], but not in mouse cortex [50].The ultrastructure of neuronal cilia also varies among cells.Notably, the 9+0 axonemal organization of microtubules was not identified throughout the cilia, and microtubules extended only to 70-86% of the ciliary length in human neurons [49].Besides, interneuronal cilia were less smooth than excitatory neurons and presented convoluted or beaded ciliary membrane sheets, suggesting increased shedding of extracellular vesicles [49].
The ciliary length of neuronal cilia is actively regulated.For example, cilia are elongated in MCHneurons when MCHR1 signaling is inhibited.Conversely, cilia are shortened when MCH pathways are activated [75].Likewise, cilia in the suprachiasmatic nucleus of mice, especially in neuromedin S-producing neurons, are regulated in a circadian matter: ciliary length oscillates from 1 to 6 μm, and ciliary abundance ranges from 10% to 40% during the circadian cycle [68].Circadian modulation of ciliary length was also observed in the nucleus accumbens, somatosensory cortex, and three hypothalamic nuclei [69].Finally, metabolic alterations, including leptin treatment, fasting, and diet-induced obesity, modulated cilium length in hypothalamic neurons [76].
Beside signaling, differentiation processes per se can alter ciliary length in neurons.This was shown in granule cells in the mouse cerebellum, which lose their cilia during differentiation [73].The deciliation process in granule cells is different from ciliary disassembly that occurs during cell division of progenitors [73] (Box 1).It involves intermediate steps, where cilia are concealed in a membrane submerged in the cytoplasm, [73] and genes important for ciliary maintenance are downregulated [72].The mother centriole docks at the plasma membrane of fully differentiated granule cells, but remains unciliated, probably due to the recruitment of the centriolar cap protein CEP97 [72].This study also reported that ciliary deconstruction in the granule cells correlated with a reduction in Hedgehog signaling [72] (Box 2).As ciliary length directly modulates ciliary signaling, control of ciliary length as well as presence and accessibility to extracellular milieu could directly impact neuronal function [77].
In the same way that ciliary length follows systematic patterns, ciliary orientation in neurons is not stochastic and, at least in some cases, seems to follow specific patterns [49,50,69].In the cortex, cilia are usually oriented toward the pia in mice [50] and within the plane of the cortical wall in humans [49].In the hippocampus, cilia are aligned to the radial axis [67].Orientation of cilia in neurons may be a specific feature of certain brain regions and not the entire brain, since no clear cilia directionality was reported in the thalamus, amygdala, hypothalamus, or in interneurons of the hippocampus [67].
All these findings suggest that neuronal cilia are dynamic and diverse, but the underlying molecular mechanisms and the physiological relevance for this apparent diversity remain elusive.It should be noted, however, that cilia in neurons are less dynamic than in neuronal progenitors (Box 1).Future work, identifying the specific molecular content of cilia in different subpopulations of neurons at different developmental and adult stages, may reveal the importance of compositional diversity of neuronal cilia and shed light on their respective functions in the brain.
list of signaling proteins in neuronal cilia keeps growing due to new techniques, including in vivo BioID-based cilia proteomics in neurons [79].
Ciliary signaling in neurons: a critical role for cAMP Analogous to the olfactory system, where olfactory signals trigger a cAMP rise following activation of the G αolf and adenylate cyclase [80] (Figure 2A), cilia-localized GPCRs in neurons also commonly signal through cAMP (Figure 2C).However, they can elicit either an increase of cAMP via G αs (DRD1 and MC4R) or a decrease via G αi/o (SSTR3, 5HT6, NPY2R, and MCHR1).Some  GPCRs do not regulate cAMP levels, but instead stimulate Ca 2+ changes via G αq/11 signaling (KISS1R) [78].Notably, cAMP synthesis in the neuronal cilia is performed by the adenylate cyclase AC3, which solely localizes to the cilia [61].
However, to date, how cilia signaling modulates neuronal activity remains elusive.This contrasts to olfactory cilia (Figure 2A), where the immediate downstream effectors of cAMP signals are well characterized, and involve the sequential activation of cyclic nucleotide-gated (CNG) channels and the Ca 2+ -activated Cl -channel, which induces neuronal depolarization [18,[80][81][82].Similarly, the cascade of events in photoreceptors, following activation of rhodopsin, is well defined (Figure 2B).It involves reduction of cGMP levels by the phosphodiesterase PDE6, followed by an inactivation of the CNG channel, leading to hyperpolarization of photoreceptors [83].
CNG channels, which play a central role in converting cAMP and cGMP levels into voltage changes in sensory neurons, have not been described in the context of neuronal cilia in the CNS [18].Thus, GPCR signaling must be decoded by different mechanisms that remain to be discovered.Besides, how ciliary signals are transmitted to the cell soma to modulate neuronal physiology remains unknown.One possibility is that the secondary messengers Ca 2+ or cAMP leak out from the cilia and bind effectors in the soma.However, this would be slow and inefficient as the number molecules are low due to the large difference between the ciliary and somatic volume.In agreement with this, reports have identified that ciliary Ca 2+ , whose concentration is six-to sevenfold higher in the ciliary compartment than in the cytoplasm, is poorly coupled to somatic Ca 2+ [84,85].Ciliary Ca 2+ levels are elevated due to the activity of Ca 2+ -permeant channels, including the heteromeric TRP channel, PKD1L1-PKD2L1, which are enriched in the cilium and counterbalance steady diffusion of Ca 2+ into the cytoplasm at its base [84,85].
How then is ciliary signaling translated into a cellular response?Advances in spatially resolved optogenetics have started to answer this long-standing question.In renal epithelial cells, the increase of cAMP in the cilium, but not in the cell body, evoked a distinct gene expression program, mediated through PKA-dependent phosphorylation of CREB in the cilia [9].Ciliary PKA is also involved in cAMP-dependent inhibition of Hedgehog signaling in the zebrafish somites [8].Whether similar processes and effectors are involved in neuronal physiology remains to be clarified.
Another major question that remains to be addressed is why some neuromodulatory GPCRs are in the cilia and some not, and what are the implications of ciliary localization of GPCRs on signaling.A recent study has identified that manipulating solely the ciliary localization of the extraretinal opsin GPCR alter its response kinetics in zebrafish spinal neurons [86].This suggests that ciliary localization per se provides a mechanism for modulating GPCR signaling [86], which may depend on the distinct lipid content of the ciliary membrane [87,88].

Cilium-synapse interactions
Most ciliary GPCRs respond either to neuropeptides or to serotonin and dopamine, which are neurotransmitters usually released within the synapse [89].Recently, it has been shown that cilia can form a synapse with serotoninergic neurons in mice [90].The so-called axociliary synapse elicited chromatin remodeling in hippocampal CA1 pyramidal neurons through a noncanonical G αq -RhoA pathway, distinct from serotonin sensing at the plasma membrane (Figure 2D).Not all neurons analyzed in this brain region form axociliary synapses, suggesting that some neurons receive different axonal and ciliary inputs.
Two recent electron microscopy studies in the human and mouse cortex investigated further cilium-synapse interactions [49,50].While neither of these two studies reported an axociliary synapse, they showed that neuronal cilia are commonly found adjacent to chemical synapses [49,50], axonal segments containing vesicles [49], and dense core vesicles [50].In the human cortex, 51% of cilia engaged in synaptic contacts and contacted up to 47 axons [49].Ciliary proximity to synapses appears, however, random and not enriched in the synapse-rich neuropil [50].Even in the absence of direct axociliary synapse, cilia would still have access to synaptic spillover of neuromodulators to the same extent as adjacent astrocytes, and, thereby, are well positioned to sense synaptic activity.Future work, looking across the nervous system at cilia connectomics and their functional implications, will be needed to understand the broad implication of cilium-axon interactions.
What is the impact of cilia on neuronal activity and animal behavior?
Ciliary function in sensory neurons is well established.Cilia detect the sensory modalities and trigger neuronal depolarization or hyperpolarization through the activity of ion channels [80,83] (Figure 2A,B).Hence, defects in ciliogenesis or ciliary dysfunction led to reduced neuronal excitability and sensory deficits, including loss of smell, retinal degeneration and blindness, and hearing impairment [14,21,22].
In contrast to sensory neurons, cilia in CNS neurons play a neuromodulatory role through controlling cellular signaling.However, studying how cilia modulate neuronal activity and animal behavior has been challenging.Given the significant role of cilia in embryonic and postnatal brain development [5,10,14,71,91,92], it is difficult to disentangle the impact of cilia on neurophysiology from a possible consequence of cilia-related developmental defects.Nevertheless, multiple groups have started to investigate the impact of cilia on neuronal physiology.
Lessons learnt from the hypothalamus So far, much of the knowledge acquired on ciliary function in neurons comes from studying the hypothalamus, where cilia seem to regulate food intake.The following observations have promoted this research: (i) conditional loss of cilia in adult mice results in hyperphagia and obesity; (ii) this phenotype is mirrored in mice with neuron-specific cilia loss, particularly in proopiomelanocortin (POMC)-expressing neurons in the hypothalamus [93,94] during development [95]; and (iii) certain ciliopathy patients, such as those with Alström or Bardet-Biedl syndrome (BBS), exhibit obesity as a major symptom [96][97][98][99].Loss of function of the BBSome, a multimeric protein complex made of several BBS proteins, affects retrograde ciliary protein trafficking and, thereby, interferes with the ciliary localization of GPCRs, including MCHR1, SSTR3 [100], NPY2R [101,102], and MC4R [103].MC4R expression in the paraventricular nucleus (PVN) of the hypothalamus controls food intake [104], and MC4R activation in MC4R-expressing PVN neurons is cilia-dependent [105].This underscores that GPCR signaling in cilia controls energy homeostasis, and supports the notion that GPCR dysregulation in BBS underlies the hyperphagia [98,99].Besides controlling GPCRs by the BBSome, the ciliary localization of ARL13B is also crucial for preventing hyperphagia and obesity development [106].In addition, mutations in the ADCY3 gene, encoding AC3, lead to obesity in both humans [103,[107][108][109] and mice [110], underscoring a critical role of ciliary cAMP signaling in the hypothalamus.
High-fat diet feeding in mice reduces ciliation in POMC neurons [111], and blocking autophagy evokes a similar effect on the ciliogenesis [111], connecting high-fat diet, autophagy, ciliary dysfunction, and obesity development.Another study further supports this by indicating that cilia in the hypothalamus control lysosomal degradation of autophagic vacuoles [95].
The hypothalamus, especially the suprachiasmatic nucleus, also controls circadian rhythm.In this context, cilia were shown to maintain the coupling of cellular oscillators in the suprachiasmatic nucleus to regulate circadian rhythms.Notably, ciliary dysfunction accelerates the adjustment to an altered light environment in a jet-lag situation through cilia-dependent Sonic Hedgehog signaling in neuromedin S-expressing neurons [68,112].

Control of neuronal excitability by cilia
Besides triggering a cascade of ciliary signaling, cilia were shown to directly modulate neuronal excitability by controlling synapse function in cortical neurons and striatal interneurons [66,113] and the neurophysiology of hippocampal neurons [114].Acute disruption of ciliary function by shRNA in cultures of cortical neurons led to increased excitatory synapses, AMPAR-mediated excitatory currents, and spontaneous firing rates [66].The application of SSTR3 agonists and antagonists also affected the levels of synaptic markers Shank3 and Vglut1 in a cilia-dependent manner [66].Besides regulating synaptic activity, neuronal cilia were shown to regulate hippocampal excitability through the action of cilia-localized PKD2L1 channels [114].Loss of PKD2L1 and electrical currents within cilia impaired ciliary maturation in mice, leading to autismlike behavioral features and seizure susceptibility [114].

Concluding remarks and future perspectives
Research over the past few decades has been instrumental in identifying cilia as evolutionary conserved organelles, playing a wide range of functions across the body and the nervous system.In turn, molecules involved in cilia biogenesis and maintenance and their association with human diseases and neurological symptoms have been identified [1,2,12,14,22].Even though research has started to clarify how cilia control neuronal signaling, excitability, and function, a broader picture is still needed of the scale of the impact of cilia on neural circuits, animal behavior, and neurological disorders.Ciliary abnormalities are increasingly observed in neurological diseases that do not fall under classical ciliopathies, such as microcephaly, neurodegeneration, and neuropsychiatric disorders.For instance, a delay in ciliary disassembly can result in neural precursor cell depletion and microcephaly, a neurodevelopmental disorder that predominantly affects brain growth [10,11,115].In human and mouse models of Parkinson's disease, neural progenitors and neurons display shortened cilia, accompanied by an elevated Sonic Hedgehog signal transduction [116].Similarly, shortened cilia were identified in schizophrenia-causing PCM1 (pericentriolar material 1) and DISC1 (disrupted-in-schizophrenia-1) mutations [117,118].These observations suggest that ciliary dysfunction may be a common feature among neurological disorders, which will require further investigation.
Even though cilia show conserved features, they are remarkably diverse and dynamic in their structure and content.However, the functional implications of cilia diversity and dynamics still need to be better understood, especially in the brain (see Outstanding questions).While parallels can be made between the mode of action of cilia in sensory systems and the CNS, compositional differences, such as the presence or absence of CNG channels, imply that ciliary signals could be interpreted in various ways in a context-dependent manner in different cell types.
The development of cutting-edge tools, including spatially resolved proteomics, optogenetics, chemogenetics, biosensors [1,79,119,120], and advances in genetic engineering are now opening new avenues for shedding light on the functional implications of ciliary diversity and signaling.Up to now, many studies have ablated cilia entirely to investigate their function.However, primarily through studying BBS mutants, it has become clear that impaired trafficking and signaling will affect ciliary function differently than changes in cilia presence or length.It is, therefore, essential to manipulate ciliary functions using different tools and approaches to generate a comprehensive understanding of context-specific ciliary functions.What are the similarities and differences between cilia in the developing and the mature brain?What can we learn from studying developmental processes about ciliary biology in mature systems?

Trends in Neurosciences
How is the signal, sensed by the cilia, transduced to the cell soma?Are there specific and conserved signaling avenues transducing ciliary signaling in the soma and what are their identities?
Cilia have been described near synapses in the cortex and have even been shown to form direct synapses with mouse hippocampal neurons.Are they common or rare among neurons?Are these contact points dynamic?Which brain area exhibits axon-ciliary synapses?What is the physiological role of cilium-synapse contacts in the nervous system?
Why are some neuromodulatory GPCRs in the cilia and some not?
How is the specificity achieved between ciliary and synaptic signaling?How is the information differentially encoded in the two locations?
What are the impacts of cilia on neuronal physiology?Which molecules are involved beyond GPCRs?To what extent are ciliary ion channels and membrane potential involved in neuromodulation?
How specific is ciliary signaling in given neuronal populations, and to what degree does signaling depend on ciliary dynamics?
What is the link between ciliary dysfunction and neurological manifestations in disorders that are not classical ciliopathies, such as microcephaly, neurodegeneration, and neuropsychiatric disorders?What is the evolutionary basis of neuronal cilia?Why do certain species lack cilia on their neurons, while others require cilia for proper brain development and physiology?

Figure 2 .
Figure 2. Ciliary signaling cascades in sensory and central nervous system neurons.(A) In olfactory sensory neurons, binding of an odorant molecule to its olfactory receptor (OR) triggers the activation of Gαolf, which stimulates AC3 and cAMP production.cAMP activates the CNG channel, leading to the entry of Ca 2+ , the Ca 2+ -dependent chloride channel (CaCC) opening, and membrane depolarization.(B) In photoreceptors, activation of rhodopsin by light stimulates the G protein transducing (G t ), which leads to cGMP hydrolysis by PDE6.Reduction in cGMP results in closure of the CNG channel and photoreceptor hyperpolarization.(C) In neurons, most cilia-localized receptors are G protein-coupled receptors (GPCRs), associated with G αs that stimulate AC3, G αi/o that inhibits AC3 or G αq/11 that stimulate Ca 2+ entry in the cells.All pathways lead to the activation of various signaling cascades.(D) In the context of the axo-ciliary synapse described between CA1 neurons and dorsal raphe nucleus axons, activation of HTR6 by serotonin stimulates RhoA through G αq/11 and leads to chromatin remodeling.
, May 2024, Vol.47, No. 5 391 Outstanding questions How diverse and dynamic are cilia in neuronal cells?What is the time scale of cilia dynamic (ranging from seconds to minutes and up to the lifetime) in an organism?What are the molecular mechanisms underlying ciliary diversity and dynamics in neuronal populations?