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Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010.

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The Neurobiology of Olfaction.

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Chapter 4Olfactory Coding in Larvae of the African Clawed Frog Xenopus laevis

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The sensing of molecules in the environment is critical to the survival of every organism. It is, therefore, hardly surprising that most animals have developed highly sophisticated olfactory systems. In contrast to other sensory systems, large portions of the genome are devoted to encode the receptors of this sensory system. The past years have seen an explosion in studies aimed at understanding the functioning of the olfactory system. These studies cover all levels of analysis—from genes to behavior. Considerable progress has been made in understanding the molecular organization of all stages of the olfactory pathway. Consequently, particular effort was spent on the question of how information contained in odorant molecules is encoded and processed at the various levels of the olfactory system, from the periphery to higher olfactory centers. As the vast majority of these studies focused on adult animals, the state of knowledge of the embryonic or larval development of olfactory systems is comparatively limited. Especially in mammals, studies focusing on the embryonic olfactory systems are inherently difficult and so far have not been carried out. In this respect, amphibians are particularly suited. Their fertilized eggs develop into free-swimming larvae before metamorphosing into juvenile animals. Ontogenetic stages of various amphibians are well characterized and easy to handle. This chapter aims to present a detailed overview of the current knowledge of the organization and function of the olfactory system of a premetamorphotic amphibian, the african clawed frog Xenopus laevis.

4.1. INTRODUCTION

Various amphibian species, including X. laevis, have been adopted as experimental animal models in numerous studies dealing with the function of the olfactory system, and numerous papers have been published about amphibian olfaction (for reviews, see Eisthen 1997, 2002; Schild and Restrepo 1998; Jørgensen 2000; Kauer 2002; Ache and Young 2005). Therefore, in this chapter, we do not describe general features of the amphibian olfactory system, but rather focus on specific new data that diverge from the current view of olfactory coding and possibly provide new insights in how the olfactory system develops.

4.2. ANATOMY AND CELLULAR ORGANIZATION OF THE OLFACTORY SYSTEM OF LARVAL XENOPUS LAEVIS

4.2.1. Principal Cavity (PC) and Vomeronasal Organ (VNO)

Larval X. laevis (Figure 4.1A) have two distinct olfactory organs: the principal cavity (PC) and the vomeronasal organ (VNO; Figure 4.1B; Hansen et al. 1998). These two olfactory organs, like those of other vertebrates (see also Chapters 5 and 6), originate from paired olfactory placodes that first become distinguishable from the surrounding ectoderm at stage 23 (stage classification according to Niewkoop and Faber 1994), and slightly later begin to invaginate to form the olfactory pits. At about stage 40, the olfactory pits start to segregate into PC and VNO (Föske 1934; Niewkoop and Faber 1994). At stage 51–52, a second cavity, the middle cavity, becomes apparent. During metamorphosis, the middle cavity strongly expands and the PC is reorganized into the adult PC. In adult X. laevis, these two cavities together with the VNO form the tripartite olfactory organ of the adult frog (Altner 1962; Föske 1934; Burd 1991; Higgs and Burd 2001; Reiss and Burd 1997a, 1997b; Hansen et al. 1998; Petti et al. 1999).

FIGURE 4.1. The main and accessory olfactory system of larval Xenopus laevis.

FIGURE 4.1

The main and accessory olfactory system of larval Xenopus laevis. (A): Larval Xenopus laevis (stage 51) The black rectangle outlines the first two stages of the olfactory system (scale bar 2 mm). (B): Horizontal overview over the olfactory epithelium (more...)

As in other amphibians, the olfactory receptor (OR) gene repertoire of X. laevis, in several respects, represents an intermediate between fish and terrestrial vertebrates (Niimura and Nei 2005; Shi and Zhang 2007; Saraiva and Korsching 2007). X. laevis has an OR repertoire of several hundred genes (Niimura and Nei 2005) and a large vomeronasal receptor (V1R and V2R) repertoire exceeding even that of rodents (Niimura and Nei 2005). ORs closely related to fish OR and those closely related to mammalian OR (see Chapter 7) are both expressed in the larval PC (Freitag et al. 1995; Mezler et al. 1999). After metamorphosis, “fishlike” ORs are expressed solely in the middle cavity and “mammalianlike” OR only in the adult PC (Mezler et al. 1999). In adult X. laevis, the PC is filled with air and serves as “air nose,” the middle cavity is filled with water and serve as “water nose” (Altner 1962). At least in larval X. laevis, V2Rs are almost exclusively expressed in the VNO (Hagino-Yamagishi et al. 2004). In X. tropicalis, VIRs have been shown to be expressed predominantly in the larval PC and not in its VNO (Date-Ito et al. 2008). The VNO is filled with water throughout the animals’ life (Altner 1962).

As in other vertebrates, the olfactory epithelia of the larval X. laevis PC and VNO are made up of three main cell types: olfactory receptor neurons (ORNs) that transmit the olfactory information from the nose to the olfactory bulb (OB) in the brain, sustentacular cells (SCs) that share properties with both glial and epithelial cells, and basal cells (BCs), including olfactory stem cells, which maintain the regenerative capacity of the olfactory epithelium (OE; Graziadei and Metcalf 1971; Graziadei 1971, 1973; Hansen et al. 1998). From stage 50 on, the OE in the PC contains two types of ORNs, ciliated and microvillar, which appear to be distributed randomly within the OE (Hansen et al. 1998). At these late stages, the PC also contains two types of SCs, one type having short microvilli and containing secretory vesicles in the apical part, and another type with kinocilia and no vesicles (Hansen et al. 1998). In the basal portion of the OE, close to the lamina propria, BCs can be found (Hansen et al. 1998). The larval PC has no Bowman glands (Hansen et al. 1998). The larval VNO has only one type of receptor cell bearing microvilli and one type of SC bearing kinocilia. The BCs show the same characteristics as those of the PC epithelium (Hansen et al. 1998).

4.2.2. Main and Accessory Olfactory Bulb (OB)

The organizational principles of the main and accessory olfactory bulb (MOB and AOB; Figure 4.1C) are conserved in different species across phyla (Hildebrand and Shepherd 1997; Rössler et al. 2002; Lledo et al. 2005). From the surface to the center of the OB, there are six discernible layers: the nerve layer, the glomerular layer (GL), the external plexiform layer (EPL), the mitral cell layer (MCL), the internal plexiform layer (IPL), and the granule cell layer (GCL). Axon terminals of ORNs of the PC synapse directly onto second-order neurons in the OB, forming spheroidal structures called glomeruli. In the premetamorphotic stages of X. laevis, the GL of the MOB is subdivided into a ventral and a dorsal part (Fritz et al. 1996; Nezlin and Schild 2000). The ventral MOB has clearly discernible glomeruli, while the dorsal MOB does not. Instead, the GL of the dorsal MOB consists of an apparently structureless fiber meshwork with some embedded fiber aggregations. About 200 periglomerular cells (PGC) reside in the GL and the EPL (Nezlin and Schild 2000). In contrast to the GL in mammals (Pinching and Powell 1971; Chao et al. 1997), where periglomerular cells (PGCs) form a wall around every glomerulus, but similar to the zebrafish (Byrd and Brunjes 1995), the glomeruli of larval X. laevis are not surrounded by cell bodies of PGC or by glia cells (Nezlin and Schild 2000; Nezlin et al. 2003). In the MOB of larval X. laevis, there are about 350 glomeruli with diameters in the range of 10–40 Ltm (Nezlin and Schild 2000; Manzini et al. 2007b).

The spatial distribution of glomeruli in the MOB revealed that the GL of the MOB of larval X. laevis is organized in at least four spatially distinct clusters: a lateral, intermediate, medial, and an additional very small cluster, situated in the very ventral part of the MOB (Manzini et al. 2007b). The lateral, intermediate, medial, and small cluster consist of about 175,70,100, and five glomeruli, respectively (Manzini et al. 2007b). Another work reports that ORN axons of larvae of identical stages terminate in up to nine different projection fields in the OB (Gaudin and Gascuel 2005). The higher number of clusters/projection fields in the work by Gaudin and Gascuel (2005) is explained by the fact that they performed a more detailed subdivision of the four bigger clusters identified by Manzini et al. (2007b).

The estimates of the number of mitral cells (MCs) in the MOB of stage 54 larvae range from about 2000 (Nezlin and Schild 2000) to about 20,000 (Byrd and Burd 1991). As Byrd and Burd counted all nuclei in the MCL/EPL, including glia and developing neurons, their number is certainly an upper estimate for the number of MCs. As the MC number obtained by Nezlin and Schild (2000) is based on backtracing from the lateral olfactory tract (LOT), it is certainly a lower limit. Granule cells (GC) of both the MOB and the AOB appeared as a compact group of cells near the paraventricular ependyma.

Axons of vomeronasal receptor neurons (VRNs) project to the AOB. The AOB is situated lateroventrally with respect to the MOB. In the AOB, the MCL is in immediate proximity to the GL, leaving only a very narrow EPL (Nezlin and Schild 2000). The glomeruli of the AOB are smaller and more densely packed than those of the MOB (Figure 4.1B). About 350 glomeruli, approximately 70 PGC, and 2500 MC have been estimated in the AOB (Nezlin and Schild 2000). Axons of MCs of MOB and AOB form the LOT and project to higher olfactory centers. How exactly MCs are connected to these is still not known.

As to the spatial propagation, first, from ORNs to glomeruli and second, from MCs to higher brain regions, a remarkable parallelization can be observed. First, individual olfactory receptor neuron (ORN) axons, as identified by dye injection into individual ORNs, bifurcate several times before entering a small number of glomeruli (2 or 3; see also Section 4.4.2). The resulting action potential splitting could be important in that it introduces correlated inputs to glomeruli in the developing system (Nezlin and Schild 2005), i.e., subsequent action potentials delivered onto the same intraglomerular postsynaptic compartment stem from the same ORN in the larval stage and possibly from different ORNs of the same ORN class in the adult. Second, all MCs connected to the same glomerulus have been shown to be synchronous (Chen et al. 2009), i.e., identical MC activity copies are sent to higher brain regions, which may be crucial for odor recognition and memory formation.

4.3. TRANSDUCTION MECHANISMS IN OLFACTORY RECEPTOR NEURONS (ORNs)

4.3.1. Main Olfactory System

In terrestrial vertebrates, the vast majority of ORNs possess the canonical cAMP-mediated transduction pathway (see Chapter 8), but a few ORN subgroups have been shown to be endowed with alternative transduction cascades (Ma 2007; Breer et al. 2006; see also Chapter 9). In aquatic vertebrates, cAMP-independent transduction mechanisms appear to be more widespread (Ma and Michel 1998; Delay and Dionne 2002; Manzini et al. 2002b; Hansen et al. 2003; Manzini and Schild 2003). This is particularly evident in larval X. laevis. The main OE of larval X. laevis contains at least two subsets of ORNs with different transduction mechanisms and different odorant specificities (Figure 4.2A and B; Manzini et al. 2002b; Manzini and Schild 2003; Czesnik et al. 2006). One subset is activated by amino acid odorants in a cAMP-independent way (Manzini et al. 2002b; Manzini and Schild 2003; Czesnik et al. 2006), while another subset responds to pharmacological agents activating the cAMP cascade. Bile acids and amines appear to be the natural odorants of this second subset of ORNs (Manzini I., unpublished data). At present, it is not known which transduction cascade is coupled to ORs sensitive to amino acids. The phospholipase C/IP3-mediated or the guanylyl cyclase D/cGMP-mediated cascades are putative candidates, but, to date, this question has not been answered. Whether the two ORN subgroups represent the two cytologically distinct ORNs (ciliated and microvillous; see Section 4.2.1.1) that have been shown to coexist in the larval PC, is not known.

FIGURE 4.2. Functional subsystems within the main olfactory system of larval Xenopus laevis.

FIGURE 4.2

Functional subsystems within the main olfactory system of larval Xenopus laevis. A: Fluo4-AM-stained acute slice preparation of the olfactory epithelium (image acquired at rest; OE, olfactory epithelium; PC, principal cavity). The black and white ovals (more...)

4.3.2. Different Transduction Mechanisms Establish Functional Subsystems

The axons of the two abovementioned ORN subsystems differentially project to the glomerular clusters present in the MOB (Figure 4.2C through E; Manzini et al. 2002b, 2007b). The subset of ORNs lacking the cAMP-dependent transduction mechanism (responsive to amino acid) projects almost exclusively to glomeruli in the lateral MOB (belonging to the lateral glomerular cluster), and the subset of ORNs endowed with the cAMP transduction cascade (mainly responsive to bile acids and amines) exclusively project to glomeruli in the medial OB (medial glomerular cluster; Figure 4.2F through H). The existence of four to nine distinguishable glomerular clusters or projection fields (see Manzini et al. 2007b; Gaudin and Gascuel 2005) suggests that the main OE of larval X. laevis possibly contains more ORN subgroups than the two that have been identified so far. As to the subsets of ORNs that project to the intermediate and the small cluster, a functional definition is still lacking.

The synaptic terminals within the glomerular clusters in the lateral and medial MOB show clear differences in the expression of presynaptic proteins (Manzini et al. 2007b). The presynaptic vesicle protein, synaptophysin, and the presynaptic membrane proteins, syntaxin and SNAP-25, are uniformly distributed in the entire GL. Synaptotagmin, another presynaptic vesicle protein, known to function as a Ca2 + sensor for the regulated exocytosis of neurotransmitters, is expressed in the lateral and partly in the intermediate glomerular clusters, but it is missing in the medial cluster (Manzini et al. 2007b). The identity of the Ca2+ sensor in the medial and the small cluster is unknown. This inhomogeneity of presynaptic protein expression is an additional striking diversity, showing the relevant difference of the ORN subsystems of larval X. laevis. These diverse subsystems with different functional relevance (amino acid vs bile acid/amine odorants) possibly emerged at different points in the evolution of the olfactory system and certainly fulfill different olfactory requirements of the larvae.

4.3.3. Accessory Olfactory System

In addition to the main olfactory system with its subsystems, larval X. laevis also have a functional accessory olfactory system. In an anatomical study, no apparent clustering of the glomeruli of the AOB has been noticed (Nezlin and Schild 2000). An electrophysiological study has shown that MCs and GCs of the AOB are spontaneously active in premetamorphotic larvae (Czesnik et al. 2001). The natural odorants/pheromones and the physiological role of the AOB in larval X. laevis remain to be determined.

4.4. ODOR-TUNING PROPERTIES OF OLFACTORY RECEPTOR NEURONS (ORNs) AND WIRING SPECIFICITY IN THE OLFACTORY SYSTEM

Following the discovery of the OR gene family (Buck and Axel 1991), a multitude of studies have been carried out to understand how ORNs express specific ORs and how these ORNs are connected to the OB (e.g., Ressler et al. 1994; Vassar et al. 1994; Treloar et al. 1996; Feinstein and Mombaerts 2004; Mombaerts 2006). From these studies, two basic principles of olfactory coding have emerged. In adult mammals, each ORN expresses one type of OR (Nef et al. 1992; Strotmann et al. 1992; Ressler et al. 1993; Vassar et al. 1993; Chess et al. 1994; Malnic et al. 1999; Mombaerts 2004, 2006; see also Chapter 7), and all ORNs that express the same OR form a class of sensory neurons and project a single unbranched axon to a single or a few glomeruli within the OB (Ressler et al. 1994; Vassar et al. 1994; Mombaerts, 1996, 2006; see also Chapter 5). These features are considered the morphological basis of chemosensory maps connecting receptor specificities to the neuronal network of the OB.

In adult mammals also the second order neurons of the OB, MCs and tufted cells (TCs), follow a characteristic glomerular innervation pattern. Each MC sends a single primary dendrite to a single glomerulus (Shipley and Ennis 1996). In addition to this primary dendrite, each MC has several secondary dendrites that protrude into the EPL, often covering large OB territories. In contrast, MCs in the turtle typically send two primary dendrites into two glomeruli (Mori et al. 1981), showing that striking differences exist between higher and lower vertebrates. Mammalian TCs often feature more apical dendrites that innervate a number of glomeruli. Similar to MCs, TCs also have secondary dendrites that extend in the EPL (Shipley and Ennis 1996). In lower vertebrates, the distinction between MCs and TCs is not as clear as in higher vertebrates. Therefore, in the following, we often use the term MCs in the sense of mitral/TCs herein.

4.4.1. Expression of Multiple Olfactory Receptor (OR) Types in Olfactory Receptor Neurons (ORNs) of Larval Xenopus laevis?

Several recent findings suggest that in larval X. laevis, a subset of ORNs express more than one type of OR. A recent study, where response profiles of individual ORNs to 19 amino acids were recorded, showed that 204 out of 283 ORNs responded differently to these stimuli (Manzini and Schild 2004). Accordingly, in the OE of larval X. laevis, there are at least 204 classes of ORNs differentially tuned to 19 amino acid odorants. Explaining such a high diversity of ORN classes by assuming one OR-type per ORN would imply the existence of a minimum of 200 ORs tuned to amino acid odorants. As there are 410 ORs in the X. tropicalis genome (Niimura and Nei 2005) and most probably a similar number also in X. laevis, it appears rather unlikely that at least 200 of them are more or less broadly and differentially tuned to amino acid odorants. The 19 amino acids could unambiguously be detected if there were 19 classes and the ORNs of each class would detect exactly one amino acid. Obviously, as few as five classes might code for 19 amino acids in case these would respond with appropriate combinations of their activities. As 10 ORN classes have been shown to be very specifically tuned to just one out of the 19 amino acids used (Manzini and Schild 2004), the first assumption appears to be more plausible. In the same study, it was observed that over ontogenetic stages, a narrowing of the response profiles of individual ORNs takes place. This analysis suggests that the abovedescribed high number of response profiles of individual ORNs could be a feature of the animals’ ontogenetic stage. This hypothesis has been reinforced by a recent theoretical analysis of the 283 response profiles to amino acids (Schild and Manzini 2004).

It is generally accepted that all ORNs that express the same OR-type (ORN classes) project their axon to a single determined glomerulus within the OB. Therefore, it should be expected that individual glomeruli of the OB have response profiles identical to those of individual ORNs. In larval X. laevis, however, this appears not to be the case. Response profiles to amino acids of individual glomeruli clearly diverge from the response profiles recorded from ORNs. A thorough comparison of the response profiles of ORN glomeruli showed that individual amino acid-sensitive glomeruli tend to be tuned much narrower than ORNs (Manzini et al. 2007a). Furthermore, in contrast to the ORN response profiles, a narrowing of the glomerular response profiles over ontogenetic stages does not take place (Manzini et al. 2007a). So far, this is the only species where ORN and glomerular response profiles of a group of odorants have been compared (see also Figure 4.3). Taken together, the response profile data of ORNs and glomeruli allow the hypothesis that immature ORNs of X. laevis, i.e., not yet fully connected to the target glomeruli in the OB, express a number of amino acid-sensitive ORs and lose most of them after having found their target glomerulus and may finally express one OR. The PC (water nose) of tadpoles of lower stages obviously has more immature ORNs not yet connected to the OB as compared to animals of higher stages, where the premetamorphic water nose has fully developed.

FIGURE 4.3. Response profiles to amino acids of individual olfactory receptor neurons and individual glomeruli of larval Xenopus laevis.

FIGURE 4.3

Response profiles to amino acids of individual olfactory receptor neurons and individual glomeruli of larval Xenopus laevis. A: ORNs of an acute slice preparation of the OE activated by application of a mixture of 19 amino acids. The ORN, indicated by (more...)

4.4.2. Axon Targeting of Olfactory Receptor Neurons (ORNs)

Atypically, in larval X. laevis, axons of individual ORNs mostly project to more than one glomerulus (Figure 4.4; Nezlin and Schild 2005). Only a minority of axons project into a single glomerulus. After entering the OB, ORN axons bifurcate into multiple axonal branches, which then typically innervate two or three glomeruli. Before entering a glomerulus, single axonal branches typically split again into sub-branches and enter the same glomerulus from opposite sides. Interestingly, the few axons that innervate only one glomerulus also split into two branches, which then project into the glomerulus from opposite sides. This means that in all cases, irrespective of the number of glomeruli innervated by one primary axon, not less than two axonal branches enter each glomerulus. It was even observed that axonal branches crossed the midline of the brain, entered the contralateral OB, bifurcated again, and innervated a glomerulus in the contralateral OB (Nezlin and Schild 2005).

FIGURE 4.4. Most ORN axons of larval Xenopus laevis project into more than one glomerulus.

FIGURE 4.4

Most ORN axons of larval Xenopus laevis project into more than one glomerulus. A: High magnification image of a biocytin/avidin-stained ORN, showing the dendrite with apical cilia and the axon. The axon disappears into a deeper layer of the slice (scale (more...)

This unexpected wiring allows several interpretations regarding its functional implication in the olfactory coding of larval X. laevis. The first one pertains to the chemosensory map, from the sensitivities of ORNs to the spatiotemporal activity pattern of OB neurons. This sensitivity-to-space map is presumably not as precise and focused in larval or embryonic stages as it is in adults. It is not known whether a similar axonal branching persists in adult X. laevis.

The atypically broad wiring properties could also be related to the abovedescribed response profile data of ORNs and glomeruli (Manzini and Schild 2004; Manzini et al. 2007a). Axons that project into more than one glomerulus could originate from broadly tuned immature ORNs, still in the process of defining their final selectivity and connecting to the respective glomerulus. In turn, the few axons that innervate only one glomerulus, could come from mature more narrowly tuned ORNs. However, this might imply that the synaptic contacts of the axons that project into more than one glomerulus are not yet fully functional, as glomeruli broadly tuned to amino acids apparently are not very numerous in the larval OB (Manzini et al. 2007a).

The fact that all axons, even those that innervate one glomerulus, split into sub-branches and enter the glomerulus from opposite sides is rather intriguing. What physiological implications could this particular branching pattern have? From what is known about axonal action potential propagation, we can assume that odor-induced axon potentials generated in a particular ORN is duplicated at every bifurcation of the axon, so that in all cases multiple action potentials enter a glomerulus almost simultaneously. These specific projection patterns could increase the fidelity of transmission to the dendrite of a projection neuron and/or alternatively excite different projection neurons. The length differences of the sub-branches can be as big as 60 κm (Nezlin and Schild 2005). The correlated action potentials must therefore arrive at their synaptic sites at slightly different times. The time delay between action potentials of the same bifurcation could be as large as 500 κs (assuming 50 κm length difference; Nezlin and Schild 2005). The temporally slightly displaced synaptic inputs could possibly enhance the synchronous activation of MCs within the target glomerulus. This might be particularly important considering that odorant-induced ORN firing rates are low in larval X. laevis (up to 20 Hz; Manzini et al. 2002a, 2002b). In higher vertebrates, synchronous activation of MCs has been put into relation with glutamate spillover in glial-wrapped subcompartments of the glomerulus (Schoppa and Westbrooke 2001). In contrast to higher vertebrates (Chao et al. 1997; Kasowski et al. 1999), glomeruli in larval X. laevis are not ensheathed by glial processes and most presumably do not include glial-wrapped subcompartments (Nezlin et al. 2003), which does not, however, preclude a few, but increasing number of PGCs. Axonal bifurcations could be an alternative way to ensure synchrony of the MCs of individual glomeruli.

4.4.3. Glomerular Wiring Specificity of Second Order Neurons

In larval X. laevis, MCs characteristically have more than one primary dendrite that project into more than one glomerulus, mainly into two or three glomeruli. None of the investigated MCs projected into a single glomerulus (Nezlin and Schild 2005). Therefore, the MC dendrites bifurcate in a way similar to the OSN projections described above. There might be a connection between the glomerular projection patterns of MCs and ORNs. In adult X. laevis, it is not known whether MCs innervate multiple glomeruli. Contrary to what is known for adult mammals (Shipley and Ennis 1996; Lledo et al. 2005), in adult turtles, MCs stereotypically innervate two glomeruli (Mori et al. 1981). This shows that glomerular projections of MCs in adult lower vertebrates can differ from those in mammals.

In mammals, the prenatal morphogenesis of MC dendrites follows a precise scheme. Immature MCs first extend undifferentiated dendrites with radial orientation toward the developing glomerular layer where ORN axons start to coalesce, innervating several adjacent glomeruli. With ongoing maturation, all but one dendrite retract and only a single primary dendrite, forming a glomerular tuft, stays in the glomerular layer. Differentiated secondary dendrites appear first in postnatal animals. Within the first two postnatal weeks, the maturation of MCs terminates (Malun and Brunjes 1996; Matsutani and Yamamoto 2000). The number of glomeruli innervated by a single MC in adult X. laevis remains to be determined.

4.5. MODULATION AND SIGNALING IN THE OLFACTORY EPITHELIUM (OE)

The OE is usually considered as the site where individual ORNs, every ORN independently from all others, detect odorants. Most studies on olfactory transduction were done in dissociated ORNs (Schild and Restrepo 1998). The OB has thus been thought of as the first level for odor-ant information processing. Consequently, the importance of multicellular interactions in the OE and the impact of efferent innervation on odorant transduction received little attention. In recent years, the importance of modulatory events in the OE is becoming increasingly evident. The list of substances that have been shown to act as signaling molecules in the olfactory neuroepithelium and/or to have influence on peripheral odorant processing includes various neurotransmitters (Bouvet et al. 1988; Vargas and Lucero 1999; Hegg and Lucero 2004; Mousley et al. 2006), nucleotides (Hegg et al. 2003; Hassenklover et al. 2008), endocannabinoids (Czesnik et al. 2007), and hormones (Arechiga and Alcocer 1969; Kawai et al. 1999; Eisthen et al. 2000). The modulation of olfactory sensory neurons by these substances match odorant sensitivity to the appetitive, arousal, reproductive, or injury state of the animal, thus impacting multiple physiological processes, including feeding behavior, mating, as well as local neuroprotective and regenerative processes.

4.5.1. Purinergic System

It has been shown that cells in the vertebrate OE express purinergic receptors (mouse: Hegg et al. 2003, 2008; larval X. laevis: Czesnik et al. 2006; Hassenklover et al. 2008). In larval X. laevis, the application of adenosine triphosphate (ATP) evokes strong increases in the [Ca2+]i in SCs (Hassenklover et al. 2008). Specifically, the responses follow a characteristic spatiotemporal pattern. The onset of the [Ca2+]i increase always occurs in the apical part of the SCs and subsequently propagates along their basal processes toward the basal lamina. This strongly suggests that the purinergic receptors may be localized on the soma of the SCs. A thorough pharmacological characterization of the purinergic responses suggests that extracellular nucleotides in the OE activate SCs via P2Y2/P2Y4-like receptors (Hassenklover et al. 2008).

In other sensory systems, e.g., in the visual, auditory, and gustatory system, extracellular nucleotides have long been known to have neuromodulatory effects and to be involved in cellular signaling (Burnstock 2007; Thorne and Housley 1996). At present, we can only speculate about the physiological role of the characteristic purinergic signaling in SCs in the OE of larval X. laevis.

In the OE of mouse, SCs are reported to express solely P2Y receptors, whereas ORNs have been shown to express both P2X and P2Y receptors (Hegg et al. 2003). Coapplication of nucleotides and odorants suppressed odorant-induced [Ca2+]i increases of mouse ORNs. Therefore, it has been suggested that purinergic receptors in the mouse OE may play a role in signaling acute damage to the OE and that ATP release of damaged cells in the OE may prevent overstimulation of cells in the olfactory system during regeneration. Additionally, purines induce the expression of heat-shock proteins in SCs, which appears to initiate a form of neuroprotection in the OE (Hegg and Lucero 2006). In contrast, in the OE of larval X. laevis, ORNs do not appear to express purinergic receptors. We have shown that in larval X. laevis, only SCs but not ORNs are activated by extracellular nucleotides. This shows that there are differences in the purinergic systems in the OE of mouse and X. laevis. In contrast to what has been shown for mice, the purinergic system in the OE of larval X. laevis appears to serve as an intraepithelial communication pathway from the very apical part of the OE to the basal lamina (Figure 4.5).

FIGURE 4.5. Schematic representation of intraepithelial signaling mechanisms and modulatory events in the olfactory epithelium of larval Xenopus laevis.

FIGURE 4.5

Schematic representation of intraepithelial signaling mechanisms and modulatory events in the olfactory epithelium of larval Xenopus laevis. Nucleotides, locally released from cells in the OE or from efferent nerve fibres terminating in the OE, induce (more...)

FIGURE 4.6. The CB1 antagonist, AM251, alters odor-evoked [Ca2+]j changes and electrical activity in individual ORNs of larval Xenopus laevis.

FIGURE 4.6

The CB1 antagonist, AM251, alters odor-evoked [Ca2+]j changes and electrical activity in individual ORNs of larval Xenopus laevis. A: Fluo4-AM-stained acute slice preparation of the OE (image acquired at rest; PC, principal cavity). The white ovals indicate (more...)

4.5.2. Endocannabinergic System (ECS)

It has been shown that in the OE of larval X. laevis, cannabinergic substances have a profound impact on odorant-induced responses of ORNs (Figures 4.5 and 4.6; Czesnik et al. 2007). In ORNs, specific CBj receptor antagonists, such as AM251, AM281, and LY320135, decrease the amplitude of odor-evoked [Ca2+]i responses and increase the latency of such signals. A comparable modulatory effect by AM251 was observed in patch clamp experiments. Spiking responses were increasingly delayed, and became longer and weaker. Consistently, application of a highly specific CB, agonist (HU210) drastically accelerated the recovery during washout and increased the percentage of recovering responses. CBrlike immunoreactivity could be localized to the dendrites of ORNs (Czesnik et al. 2007). ORN dendrites are certainly the appropriate compartment for partially decoupling the transduction compartment from the transformation compartment. The effects of cannabinoids on odor-evoked ORN responses described above, may be explained by the dendritic localization of CBj receptors. X. laevis is the first species where such an effect has been shown. The underlying physiological processes of the endocannabinergic system in the OE remain to be elucidated.

Recently, several studies have been published dealing with the influence of the nutritious status on the neurophysiology of olfactory information processing and vice versa, whereby some of the phenomena could indirectly be attributed to the effects of modulators like orexin in the rat OB or neuropeptide Y in the OE (Caillol et al. 2003; Apelbaum et al. 2005; Hardy et al. 2005; Mousley et al. 2006). The endocannabinergic system is known to be involved in food intake and energy homeostasis (Di Marzo and Matias 2005). Indeed, in several species, brain endocannabinoids seem to act as orexigenic mediators (Valenti et al. 2005; Soderstrom et al. 2004; Kirkham et al. 2002; Di Marzo et al. 2001). Our findings together with the abovementioned observations and the known role of olfaction in food detection certainly support the idea that the endocannabinergic system may play an important role in the response of organisms to their nutritional status. The main effect may be that the hungrier an animal is, the more sensitive are its ORNs. Similar effects may exist in other sensing systems.

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