Review
From progenitors to integrated neurons: Role of neurotransmitters in adult olfactory neurogenesis

https://doi.org/10.1016/j.jchemneu.2011.05.006Get rights and content

Abstract

Adult neurogenesis is due to the persistence of pools of constitutive stem cells able to give rise to a progeny of proliferating progenitors. In rodents, adult neurogenic niches have been found in the subventricular zone (SVZ) along the lateral ventricles and in the subgranular zone of the dentate gyrus in the hippocampus. SVZ progenitors undergo a unique process of tangential migration from the lateral ventricle to the olfactory bulb (OB) where they differentiate mainly into GABAergic interneurons in the granule and glomerular layers. SVZ progenitor proliferation, migration and differentiation into fully integrated neurons, are strictly related processes regulated by complex interactions between cell intrinsic and extrinsic influences. Numerous observations demonstrate that neurotrasmitters are involved in all steps of the adult neurogenic process, but the understanding of their role is hampered by their intricate mechanism of action and by the highly complex network in which neurotransmitters work. By considering the three main steps of olfactory adult neurogenesis (proliferation, migration and integration), this review will discuss recent advances in the study of neurotransmitters, highlighting the regulatory mechanisms upstream and downstream their action.

Highlights

► Neurogenesis persists in adult mammalian brain leading to integration of functional new neurons. ► This process is regulated at different steps: cell proliferation, migration and integration. ► Neurotransmitters act in a complex network to regulate these adult neurogenic processes.

Introduction

Besides their classical role in chemical communication, neurotransmitters are reported to act very early during neurogenesis playing important functions on cell development (Behar et al., 1994, Behar et al., 1999, LoTurco et al., 1995).

Neurogenic processes, classically thought to occur only during brain development, persist in selected regions of the adult mammalian brain. During adulthood, the production of new functional neurons takes place in the hippocampal dentate gyrus and in the subventricular zone-olfactory bulb (SVZ-OB) system (Ming and Song, 2005). In the adult hippocampus, neurogenesis generates additional excitatory granule cells, whereas in the SVZ of the lateral ventricle neurogenesis gives rise mainly to inhibitory interneurons destined for the OB (Fig. 1). Several studies suggest that neurogenesis in these regions is modulated by experience and correlated to learning and memory functions (Zhao et al., 2008a). However, the role of neurogenic processes in the context of the mature brain is still elusive. Both forms of adult neurogenesis progress via division of radial glia-like stem cells into rapidly dividing intermediate progenitor cells and production of post-mitotic cells. In the SVZ-OB system a prominent migratory process takes place: neuronal progenitors travel along the rostral migratory stream (RMS) from the SVZ to the OB and accessory OB (AOB), where they differentiate and integrate functionally into local networks (Luskin, 1993, Oboti et al., 2009, Peretto et al., 2001).

Adult neurogenesis is a complex process that must be regulated at different stages of cell development including proliferation, migration and integration, in order to generate and functionally incorporate the new neurons. The final success of this event, which may sustain both physiological adaptation and repair processes (Lledo et al., 2006, Taupin, 2006, Vandenbosch et al., 2009), results from the interaction between intrinsic neuronal growth properties and regulatory molecules in the microenvironment. Moreover, external conditions including sensory, motor or social stimuli, as well as pathological conditions, may influence different steps of neurogenesis (Deng et al., 2010, Zhao et al., 2008b, Lazarini and Lledo, 2010;Whitman and Greer, 2009) and be mediated by context-dependent modulation of specific signals that include neurotrophins and neurotransmitters.

In this context, this review will cover recent progress on the impact of the major classes of neurotransmitters on adult neurogenesis, focusing on the SVZ-OB system. We will cover the role of neurotransmitters in regulating the different stages of adult OB interneuron development, from proliferation to migration and integration.

Section snippets

Cell proliferation

Within the adult SVZ, GFAP-expressing astrocyte-like cells, also called B-type cells, act as neural stem cells (Doetsch et al., 1999). These cells are slowly dividing progenitors which give rise to transiently amplifying progenitor cells, or C-type cells, expressing the epidermal growth factor receptor (EGFR). In turn, C-type cells generate neuroblasts, neural progenitor cells also called A-type cells, which express doublecortin (DCX) and PSA-NCAM. It is these neuroblasts that travel along the

Migration

Neuroblasts originated in the SVZ migrate tangentially along the rostral extension of the SVZ to reach the OB. In the adult, a characteristic “chain” migration involving bulks of cells sliding into the longitudinally oriented glial tubes has been described (Lois et al., 1996, Peretto et al., 1997) (Fig. 1B). Although tangential migration begins at birth, the glial tubes do not form until the third postnatal week. In those first weeks the glial processes of astrocytes form a relative homogeneous

Integration

Once in the bulb, newborn cells differentiate mainly into olfactory interneurons. Most of the SVZ-derived cells (90%) contribute to granule cell (GC) population while a smaller part migrate further to differentiate in periglomerular cells (PGCs) in the glomerular layer (Fig. 1C). Not all the cells that reach the OB survive; about half of newborn GCs and PGCs are eliminated within a time window that extends from 15 to 45 days after they are born in the SVZ (Petreanu and Alvarez-Buylla, 2002,

Concluding remarks

The literature addressed to the role of different types of neurotransmitters in the control of adult neurogenesis is growing rapidly. At present, the complexity of the process is clearly very high and our understanding incomplete (Table 1). The difficulty in approaching such issue, resides in the mode of action, that depend on neurotransmitter receptor composition, affinity, distribution, desensitization profiles, compensatory and reuptake mechanisms, and intracellular pathways. The same

Acknowledgements

This work was supported by Compagnia di San Paolo (Neurotransplant 2007-0660). Serena Bovetti is recipient of a fellowship sponsored by Regione Piemonte Azione A.

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