Review articleTowards the classification of subpopulations of layer V pyramidal projection neurons
Introduction
The original classification of most cerebral cortical neurons originated in the previous century. Neurons were characterised based on their size, shape and dendritic branching pattern as they appear on Golgi-stained preparations (Golgi, 1886, Ramón y Cajal, 1911, Lorente de No, 1949). The basic terminology for the identification of cortical neurons (e.g. pyramidal, stellate or granular cell, etc.) is still in use today. It was not until the advent of reliable tracing methods that connectivity became a pertinent and useful criterion. The principal neuronal types of the cerebral cortex are the excitatory pyramidal cells, which project to distant targets, and the inhibitory non-pyramidal cells, which are the cortical interneurons (Peters and Jones, 1985). These different classes of neurons originate from distinct regions. Pyramidal neurons are generated in the cortical neuroepithelium and migrate radially to reach the cortex following an inside–out gradient (Rakic, 1988), whereas most of the interneurons originate from the basal telencephalon and migrate to the cortex through tangential migration (Parnavelas, 2000, Marín and Rubenstein, 2001). Histochemical and immunohistochemical analysis revealed further details especially of the different types of interneurons (Markram et al., 2004). A list of relatively simple but reliable markers aided the identification of different interneuron classes, and these markers are still used today (Somogyi and Klausberger, 2004). Projection neurons have been further classified by the laminar position of their cell body, morphology, electrophysiology and hodology (Toyama et al., 1974, Peters and Jones, 1985), but there are relatively few neurochemical markers available for their identification. Classification of central nervous system (CNS) regions has been advanced in recent years by exploiting modern mouse molecular genetics. Markers are useful for classification, but also they are equally interesting for understanding development. The specific combination of transcription factors defines neuronal fate, and their combinatorial expression pattern closely correlates with neuronal diversity (Gray et al., 2004). Genes which regulate the production of cortical cell types have been identified (Guillemot et al., 2006, Wu et al., 2005, Hevner et al., 2006), however, the molecular profile within pyramidal cell populations in the cortex remains relatively undeveloped. The reason behind this might be the lack of integrated approaches that utilise several of the classification criteria (hodology, morphology and physiology) synchronously. Approaches employing methods where all these components are viewed in conjunction have yielded the greatest progress (Migliore and Shepherd, 2005, Nelson, 2005, Sugino et al., 2006). We wish to give an update on the efforts made in this field by reviewing recent studies on subtypes of layer V pyramidal neurons in the rodent cerebral cortex. Pyramidal cells of this class provide an exceptional model system to test ideas on cell classification and to study neuronal specification within the same cortical lamina.
Section snippets
Layer V pyramidal cells: an accessible model for the study of target selection, dendritic and physiological differentiation
Within layer V of the adult rodent cortex, pyramidal neurons with different soma size can be distinguished. Neurons with smaller sized soma tend to occupy the lower portion of layer V (Vb), whereas cells with larger soma tend to reside within the upper sector (Va). However, the location is not an absolute predictor since the two types of somas mingle with one another and there is a considerable overlap between them within layer V. The different soma sizes can be linked to distinctions in their
The general neurobiological relevance of the model
An obvious question is whether this system is general across different cerebral cortical areas in rodent, and whether it can be found in various different species including primates. While most experiments were performed in rat visual cortex, the existence of two similar types of layer V neurons were demonstrated in auditory, motor and somatosensory regions as well (Chagnac-Amitai et al., 1990, Games and Winter, 1988). In the adult rat cortex, the particular cortical area determines the
The diversity of somatodendritic morphology of layer V neurons
Although pyramidal cells share numerous common features within layer V, they are very heterogeneous in their somatodendritic morphology (Schofield et al., 1987, Hallman et al., 1990). The basic classification of type I (tufted) and type II (non-tufted) has proven to be helpful but oversimplified. At least two clear subclasses of tufted populations have been identified. One subclass possessed a simple main apical dendrite reaching layer I and terminating in a single tuft, while another has side
Electrophysiological classification
The electrophysiological distinctions between the two major types of layer V neurons have been described by Kasper et al. (1994) using sharp electrode recording. Prelabelling with fluorescent latex microspheres enabled Kasper et al. (1994) to record from neurons with identified projections and correlate the electrophysiological parameters to the somatodendritic morphology and projection target. The development of subthreshold and action potential properties of layer V neurons recently have been
Layer V marker gene expression pattern
The quest of finding neurochemical markers for layer V projection neurons started at the time when layer V neurons were being classified into type I subcortically projecting and type II callosally projecting neurons (Stanfield and Jacobowitz, 1990, Larkman and Mason, 1990). There are numerous layer V-specific protein markers. To integrate with existing classification schemes, here we describe the markers that have been demonstrated to be type-specific by combining retrograde labelling with in
Do GABAergic projection neurons contribute to subcortical or callosal connectivity?
It has been shown that mature GABAergic neurons can develop long range projections intracortically (Fabri and Manzoni, 1996), and the vast majority are immunoreactive for somatostatin, neuropeptide Y and nitric oxide synthase (Tomioka et al., 2005). In developing rat neocortex, GABAergic neurons can even travel across the corpus callosum (Kimura and Baughman, 1997). At present, the general view is that roughly 1% of the callosally projecting neurons are GABAergic in the mature nervous system of
Transgenic mice expressing fluorescent proteins could provide useful tools to characterise layer V subclasses
GABA-containing interneurons are well-defined by proteins such as calbindin, calretinin, parvalbumin, neuropeptide Y, vasoactive intestinal peptide, somatostatin and cholecystokinin (Markram et al., 2004, for review). Although no specific type of interneuron can be defined by a single marker, some types express specific combinations of different markers. With the continuous isolation of molecular tags specific for layer V pyramidal neurons, we can refine the classification of projection neurons
Co-localisation studies suggest the existence of several subclasses of layer V neurons
An important aim of this study is to unify molecular classification with other aspects of layer V neuronal classification in adult and during development. It is important to correlate the combination of expressed genes with projection targets and specific somatodendritic morphology. Co-localisation studies on OTX-1 and ER81 indicate that the two markers are not expressed within the same postnatal layer V neurons (Hevner et al., 2003). Using retrograde labelling and immunohistochemistry, we have
Dual projections can be established in numerous combinations
Within any single layer of the cortex, there are numerous morphological subtypes with different cortical (intracortical or intercortical) and subcortical connectivity (Thomson and Bannister, 2003). While it is clear that there are stereotypic patterns in the connections from the earliest stages of development, it is also clear that the idea of single destination has to be abandoned. Throughout the developing CNS, promiscuous initial connections are pruned back to few targets or eliminated
Summary
Our challenge is now to understand the combinatorial effect of lineage- and area-specific gene expression profiles. These fundamental components drive neurogenesis, differentiation and regional cortical connectivity. Potential molecular markers for layer V projection neurons are continually being found. Correlation of these markers with other aspects of neuronal phenotype will offer a more comprehensive classification of layer V neurons. More importantly, markers will reveal mechanisms by which
Acknowledgements
The review is based on a talk given by ZM at the meeting held on Neuronal Differentiation in Cortical Development at Icho-kaikan in Osaka University, Suita, Osaka, in September 16–17, 2005. This meeting was held to mark the end of the Human Frontiers Science Program Grant (RG 107/2001) by Nobuhiko Yamamoto, Etienne Audinat, Daniel Lavery and Zoltán Molnár. Consortium members very much valued the interactions during the period of the grant which resulted in development of numerous collaborative
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