Trends in Neurosciences
Volume 31, Issue 8, August 2008, Pages 392-400
Journal home page for Trends in Neurosciences

Review
Origin and function of olfactory bulb interneuron diversity

https://doi.org/10.1016/j.tins.2008.05.006Get rights and content

In adult rodents, subventricular zone (SVZ) astrocytes (B cells) function as primary progenitors in the generation of new neurons that migrate to the olfactory bulb (OB), where they differentiate into multiple types of interneurons. It has been generally considered that individual adult SVZ stem cells are capable of generating different types of neurons and glial cells. However, recent studies indicate that these adult SVZ primary progenitors are heterogeneous and predetermined to generate specific types of neurons. Surprisingly, OB interneurons are generated by stem cells not only in the walls of the lateral ventricle facing the striatum but also in the rostral migratory stream and walls of the lateral ventricle facing the cortex and the septum. SVZ B cells in different locations within this extensive germinal region generate different kinds of interneurons. General physiological characteristics of major classes of OB interneurons have begun to emerge, but the functional contribution of each subtype remains unknown. The mosaic organization of the SVZ offers a unique opportunity to understand the origin of interneuron diversity and how this assortment of neurons contributes to plasticity of postnatal olfactory circuits.

Introduction

The olfactory bulb (OB) of the adult mammalian brain continues to receive new neurons throughout life [1], but how these newborn cells shape olfaction remains unclear. The first synaptic relay in the olfactory system occurs in the OB [2]. Odor discrimination begins with the binding of odorant molecules to receptors expressed by olfactory sensory neurons (OSN) in the nasal epithelium. There, individual OSNs express one type of olfactory receptor from a large family of genes [3]. Although broadly distributed in the olfactory epithelium, OSNs expressing the same receptor project onto specific glomeruli in the OB (Figure 1). Their axons contact the primary dendrites of mitral and tufted cells, most of which project an axon outside the OB and primarily into olfactory cortex [4]. The segregation of odorant information at the level of OSNs and glomeruli has been suggested as a fundamental first stage in olfactory discrimination 2, 4. This, however, does not fully explain how odors are identified, because olfactory receptors are promiscuous and can bind multiple odorants, activating groups of glomeruli. Rather, the identity of the odorant is encoded by the relative levels of activation of multiple glomeruli [5]. Thus, the processing of olfactory information in the OB results in a complex and dynamic activation of mitral and tufted cells that receive information from multiple glomeruli [5]. Mitral and tufted cells interact with a very large population of local circuit interneurons that use γ-aminobutyric acid (GABA) as their main neurotransmitter [4]. In the OB, the ratio of local GABAergic interneurons to excitatory neurons (100:1 [4]) is much higher than in other parts of the brain, such as the neocortex (1:5 [6]). The balance between excitation and inhibition in the OB is relatively conserved across mammalian species, suggesting that the inhibitory neurons play essential roles in the processing of olfactory information. The neurons that form these inhibitory circuits are chemically and electrophysiologically diverse. Intriguingly, these different OB inhibitory neurons continue to be replaced during juvenile and adult life, whereas olfactory circuits are already in operation. This raises very basic questions on the origin of the different types of neurons in the developing and adult OB and about their function.

Adult neurogenesis has been evolutionarily conserved from reptiles to mammals, and the analogous replacement of local interneurons also appears to occur in central processing regions of insects [7] and crustaceans [8]. In mammals, new OB interneurons originate from a germinal region known as the subventricular zone (SVZ), on the walls of the lateral ventricles [1] (Figure 1). Neural stem cells that function as primary precursors in the SVZ correspond to type B cells, a subpopulation of slowly dividing cells that has the morphology, ultrastructure and markers of astrocytes [9]. Type B cells produce type C cells, which divide rapidly to produce young neurons, also known as neuroblasts or type A cells. These neuroblasts in turn migrate tangentially in chains, forming an extensive network of pathways in the SVZ. These local SVZ chains merge anteriorly to form the rostral migratory stream (RMS), a large migratory pathway leading into the OB (Figure 1). Within the OB, young neurons mature into various subtypes of local inhibitory interneurons 10, 11, 12, 13, 14.

There are two principal types of adult-born OB interneurons: granule cells (GC) found in the granule cell layer (GCL), and periglomerular cells (PGC) located in the glomerular layer (GL) (Figure 1, Figure 2). A recent study suggests that a subpopulation of interneurons in the external plexiform layer (EPL) is also produced postnatally [15]. Adult-born GCs can be subdivided into distinct populations by morphological criteria. Superficial GCs whose dendrites target primarily the superficial lamina of the EPL are believed to establish synapses with tufted cells [4], whereas deep GCs contact mostly the dendrites of mitral cells in the deep lamina of the EPL 4, 16, 17. As mitral and tufted cells project into different regions of the olfactory cortex, these two populations of GCs might be part of separate neural circuits for olfaction. The tufted–GC circuit might mediate low-threshold perception of odorants [18] by intrabulbar association [19], whereas mitral–GC interactions might be important for odor discrimination [20] (see Box 1). Adult-born PGCs can be subdivided into three nonoverlapping populations based on their immunoreactivity to tyrosine hydroxylase (TH), an enzyme required for dopamine synthesis, or immunoreactivity to the calcium binding proteins calbindin (CalB) or calretinin (CalR) [21]. In the mouse, GCs and all three PGC subpopulations express GABA 22, 23, whereas only GCs and TH+ PGCs were found to be GABAergic in the rat [23]. However, it is still unclear whether cell populations defined by these marker genes correspond directly to cell populations defined by morphological [24] or electrophysiological criteria [25].

Until recently, it was not known how multiple subtypes of local interneurons – each with different physiological, morphological and molecular properties – were generated during development or in the adult. Furthermore, it was unclear how the stereotyped connections of OB interneurons are established despite their constant turnover. In this review, we discuss recent results that point to distinct origins of local interneurons formed postnatally, their diverse modes of maturation and various functions once integrated. Today it is clear that all OB microcircuits depicted in Figure 2 are affected by the continuous neuronal turnover throughout life. By better understanding the origin of this complexity, we can begin to uncover how the constant renewal of the OB inhibitory network might be regulated and contributes to the processing of olfactory information.

Section snippets

Embryonic origins of olfactory interneurons

Bulbar interneuron production begins as early as embryonic day (E)14 [26]. It was thought that OB interneurons, like cortical interneurons, were generated from subpallial structures. Several studies supporting this hypothesis have suggested that the adult SVZ is derived from the lateral ganglionic eminence (LGE) of the embryonic telencephalon. For example, LGE progenitors grafted into the LGE or adult SVZ produce neuroblasts that migrate to the OB; these neuroblasts mature into interneurons

The temporal and regional production of olfactory interneurons

The cell bodies of neural stem cells line the embryonic and early postnatal ventricular system, forming a ventricular zone (VZ). Within the first couple of weeks of postnatal life in mice, most neural progenitors are depleted from this region as a layer of postmitotic ependymal cells replaces the VZ. Neural stem cells persist only in restricted regions, such as the adult SVZ. As the brain matures, these stem cells transform from radial glial cells into astrocytic SVZ type B cells [35].

Cell-autonomous specification of OB interneuron diversity

Both genetic determinants and environmental factors might regulate OB interneuron identity and function. This age-dependent regulation can be attributed either to age-dependent changes in SVZ progenitors or to progressive modifications in the OB milieu that influence the final maturation of newly born neurons. To discriminate between these possibilities, LGE/SVZ progenitors were transplanted into homochronic or heterochronic environments 22, 40. Grafted cells preferentially acquired phenotypes

Synaptic integration of newborn interneurons

It remains unknown how the different subtypes of interneurons produced by the heterogeneous set of neural stem cells integrate into OB circuits and contribute to its physiology. However, some knowledge has begun to emerge on the general electrophysiological properties of GCs and PGCs during their maturation. Migrating neuroblasts express early extrasynaptic GABAA receptors [49] and establish functional synapses only after they mature and integrate into circuits of the OB. Synapses in maturing

Functional diversity of newborn interneurons

The different functional roles of postnatally generated subtypes of OB interneurons such as deep or superficial GCs or PGCs expressing TH, CalR or CalB 22, 43, 46 remain unclear. These cell types differ not only in their neurochemistry, marker gene expression and location in the OB but also in their morphology [21], synaptic properties [60] and rate of turnover 61, 62. It has been proposed that the different PGC subtypes serve specific functions [23]. PGCs establish reciprocal dendrodendritic

Concluding remarks

It is now clear that OB interneurons are generated in a large germinal region encompassing areas of the pallium and subpallium including the RMS, the striatal and septal ventricular wall. Different interneuron subtypes are derived from different territories within this extensive area of postnatal germinal activity. In addition, some types of interneurons are preferentially produced during a specific period of development or postnatal life. The production of different neuronal subtypes from

Acknowledgements

Additional references relevant to this subject are included in the cited studies; they could not be included in this review because of space limitations. The Lledo laboratory is supported by the Fondation pour la Recherche Médicale, Association Française contre les Myopathies, Fédération pour la Recherche sur le Cerveau, Agence Nationale de la Recherche (ANR-05-Neur-028–01), the Groupe Arpège and the Fondation NRJ-Institut de France. This laboratory is also a member of the Network of European

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