Getting connected in the dopamine system
Introduction
Dopaminergic neurons located in the ventral midbrain are essential for the control of cognitive and motor behaviors and are associated with multiple psychiatric and neurodegenerative disorders. Three anatomically and functionally distinct subgroups of mesodiencephalic dopamine (mdDA) neurons have been identified (Carlsson et al., 1962, Dahlström and Fuxe, 1964, Hökfelt et al., 1984). The lateral A9 group corresponds to neurons of the substantia nigra pars compacta (SNc). These neurons have prominent projections to the dorsal striatum (the so-called nigrostriatal or mesostriatal pathway) and are involved in the control of voluntary movement. SNc neurons have been the subject of intense study since their selective degeneration is responsible for the motor defects observed in individuals suffering from Parkinson's disease (PD) (Savitt et al., 2006, Sulzer, 2007). The medial A10 and A8 groups define the ventral tegmental area (VTA) and retrorubal field (RRF), respectively. Neurons in these subgroups prominently innervate the ventromedial striatum and prefrontal cortex (PFC), as part of the mesocorticolimbic system, and are involved in the regulation of emotions and reward. Defective dopaminergic transmission in the limbic system has been implicated in the development of drug addiction, depression and schizophrenia (Nestler, 2000, Robinson and Berridge, 1993). The important link between mdDA neurons and profound neurological and neurodegenerative disorders has triggered an intense study of mdDA neuron function, including of their development. The development of mdDA neurons is a complex, multi-step process. It includes early developmental events such as cell fate specification, differentiation and migration and later events including neurite growth, guidance and pruning, and synapse formation. Significant progress has been made in defining some of the early events. This includes the identification of key transcriptional determinants regulating regional specification and cellular differentiation (Smidt and Burbach, 2007). Although later stages of mdDA neuron development are less well understood, recent studies have begun to identify cellular and molecular signals thought to be important for the establishment of mdDA neuronal connectivity. The purpose of the present review is to summarize our current understanding of the ontogeny and anatomy of mdDA axon projections, to highlight recent progress in defining the cellular and molecular mechanisms that underlie the formation and remodeling of mdDA circuits, and to discuss the significance of this progress for understanding and treating situations of perturbed connectivity in the mdDA system.
Section snippets
Ontogeny of mdDA projections
The estimated number of neurons in the adult bilateral mdDA system (A8–A10) ranges from 20,000–30,000 in mice to 400,000–600,000 in human. These neurons give rise to prominent forebrain projections and receive inputs from various other brain regions (Bjorklund and Dunnett, 2007). Work in several different species and employing diverse experimental approaches (e.g. immunohistochemistry, axon tract tracing or XFP-labeled mice) has provided valuable insight into the development of mdDA circuits.
The cellular basis of mdDA axon guidance
Much of what we know today about the molecular and cellular mechanisms regulating neuronal network formation derives from elegant tissue culture experiments. For example, the founding members of several different guidance cue families have been identified on the basis of chemotropic activities observed in co-culture systems that combine projection neurons and their targets (Tessier-Lavigne and Goodman, 1996). Similarly, tissue culture studies have provided a wealth of information on how the
The molecular basis of mdDA axon guidance
The formation of neural circuits during development depends on a precise series of molecular and cellular events. Once neurons have migrated to their final destination, they elaborate axons and dendrites along predetermined routes in the developing embryo to establish highly specific connections with their targets. This not only requires the proper growth and guidance of extending axons and dendrites but also their subsequent branching and pruning, and the formation of functional synapses.
Parkinson's disease and cell-replacement strategies
Studies of the cellular and molecular mechanisms that underlie neuronal network formation are not only essential for developing effective repair strategies for neurodegenerative disorders such as PD but may also provide insight into the onset and progression of these disorders. For example, microarray studies comparing gene expression profiles in the midbrain and striatal regions of control and PD patients or PD mouse models reveal marked differences in the expression of axon guidance cues and
Concluding remarks and future directions
Despite the fact that structural and biochemical changes in mdDA circuits have been associated with multiple psychiatric and neurodegenerative disorders, our understanding of the mechanisms that regulate the formation and maintenance of these circuits is rather rudimentary. Recent studies have begun to define the cellular and molecular signals that instruct mdDA axons to establish highly stereotypic connections to the forebrain. However, most of what we know today about mdDA axon growth and
Acknowledgements
We thank Marten Smidt, Peter Burbach, Sharon Kolk and Asheeta Prasad for reading the manuscript. Work in the laboratory of the authors is supported by grants from the Netherlands Organization of Scientific Research, Dutch Brain Foundation, the International Parkinson Foundation, the Human Frontier Science Program and ABC Genomics Center Utrecht. RJP is a NARSAD Henry and William Test Investigator.
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