Abstract
In the absence of external spatial cues, dendritic arbors of neurons grown in vitro approximate those observed in situ. Absent, however, from these culture models is patterned orientation of dendritic trunks, and variation of branch geometry that provide identifiable characteristics of the cytoarchitecture of the intact brain. Although astroglia are present during key stages of dendritic development in vivo, little is known about whether local interactions with glia shape dendritic growth. Astroglial cells are good candidates for this kind of regulation because they can exert control over the formation of synapses, an event correlated with the maturational state of the dendrite. The present review highlights some key findings from vertebrate model systems offering evidence that astroglia can contribute to the shape, and growth, of the dendritic arbor. Drawing from our recent work using a co-culture system composed of neurons growing in differential contact with astroglia, we discuss findings that suggest: 1) growth of dendrites, and addition of synapses, can be independent; further, while astroglia promote synapse formation, they inhibit dendritic growth; 2) astroglia mediate dendrite growth through both paracrine, and contact-dependent mechanisms; and 3) astroglia appear to impose pattern by constraining the growth of dendrites within their zones of influence.
Keywords
- dendrite morphogenesis
- neuron-astroglia interactions
- dendritic development
- dendritic patterning
- dendritic growth
1. Introduction
The size and shape of the dendritic arbor is a key factor in determining the connective potential of a neuron. While programs intrinsic to the neuron itself can instruct the general morphology of the dendritic arbor [1], it has long been recognized that the form dendrites take as they mature is under significant influence from extrinsic factors [2, 3]. The complexity of extrinsic influences, and the collective impact they have upon dendritic architecture, is evident when one compares the spatial patterning of dendritic arbors that have developed
But while fundamental questions remain, new tools are being brought to bear in this area of active investigation, and a series of insights have unfolded over the last decade. For example, interactions within, and between, neurons are one important source of cues involved in ontogenesis of the dendritic arbor. The mechanism of “self-avoidance” between dendrites within a given arbor can help establish appropriate spacing of branches (for review, see [5]). Similarly, segregation of branch territories has also been recognized as important in understanding how the dendritic arbors of a single type, or class, of neuron within a brain region are arranged in a territorial configuration. Such an arrangement optimizes dendritic capture of incoming afferents and is now understood at a mechanistic level [6, 7]. It is hard to envision how these homotypic mechanisms contribute to the cases where branching pattern and density vary stereotypically along a single primary stalk of the arbor, however.
The hypothesis that astrocytes might also shape dendrites has received less attention. In 2010, Procko and Shaham proposed that glial cells might play such a role, although, at that time, direct evidence in vertebrate systems was lacking [8]. Mounting evidence, however, demonstrated that interactions between neurons and astroglia were crucial to other aspects of dendritic development [9, 10, 11]. Astroglia secrete factors that facilitate synapse formation, both in terms of the onset [12, 13, 14, 15, 16] and of rate [17, 18]. Because immature dendrites are not receptive to innervation [19], these synaptogenic effects could imply an astroglial contribution to dendrite maturation. In addition, astroglia produce factors that modulate synaptic efficacy [20] and regulate synapse pruning [21]. Moreover, a number of growth factors have been identified that selectively alter dendritic, but not axonal growth, of forebrain neurons, e.g., [22, 23] and these factors may be produced, or regulated by astroglia [24, 25]. Collectively, these findings point toward mechanisms whereby astroglia could influence the competence, or developmental state, of the dendrite. It is therefore becoming increasingly important to characterize these effects in more detail so as to determine the roles of astroglia as regulators of synapse formation versus sculptors of dendritic arbor size and shape.
In this regard, data from two human neurodevelopmental disorders, Rett Syndrome and Fragile X mental retardation, implicate astroglia as a regulatory influence on the growth of dendrites [26, 27]. In Rett Syndrome, single-gene mutations in the X-linked transcription factor methyl-CpG-binding protein 2 (
2. Dendritic arbors of isolated neurons grown in vitro exhibit features that are intrinsically determined and lack those features patterned by extrinsic influences
The first microscopic views of the intact hippocampus, impregnated with Golgi stain, illustrated the extent to which dendritic arborization is patterned (Figure 1A). This distinctly polarized arbor, with zonal variation in branching pattern, also forms in organotypic slice cultures, a method that preserves some populations of afferents, astroglia, and microglia [34] as dendritic outgrowth and maturation takes place [35]. In contrast, dissociated cultures of hippocampal neurons isolated from embryonic rat brain remove spatial cues that come from organized inputs and contain predominantly neurons with an excitatory phenotype. These cells generate MAP2 positive dendritic arbors that proceed to form post-synaptic specializations expected of pyramidal cells
3. Both the presence of astroglia and factors derived from astroglia alter the spatial patterning of dendritic arbors grown in vitro
3.1. Effects produced by secreted, soluble factors present in media conditioned by astroglia
Further evidence of the importance of developmental cross-talk between astroglia and dendritic morphogenesis emerged. Astroglia native to the cortex promoted dendrite formation of cortical neurons more effectively than astroglia from other regions of the brain [39, 40, 41, 42]. These studies supported the hypothesis that astroglia could influence dendritic growth in a brain-region specific manner. Taken together, these findings suggest that the developmental interactions between astroglia and the forming dendritic arbor might be multiple and significant.
It was in this context that we sought to observe dendritogenesis
What was unexpected, however, was that the dendritic arbors that formed in the glial-deprived neuron cultures were more extensive than those of neurons grown in an astroglial co-culture, with significantly more primary and higher-order branches [43]. These findings revealed that astroglia exert two effects on dendritic development that seem paradoxical. On the one hand, astroglia were permissive to synapse formation, and on the other hand, their presence limited dendritic outgrowth. A similar inhibitory effect by astroglia has been reported to occur in brain stem neurons
Thrombospondin (TSP) is the synaptogenic factor that is produced by astroglia and promotes the formation of presynaptic contacts onto dendrites both
3.2. Effects mediated by local contact between astroglia and neurons
Co-plating neurons and astroglia on the same coverslip offers opportunities for local interaction between the two cell types that could involve signals both soluble and contact-dependent. In our work, we have observed that neurons in full contact with astroglia had dendritic arbors with reduced size compared with neurons that did not contact astroglia at all. These effects could be mediated by the same mechanism as described earlier, but given that the neuron has grown while adhering to an astroglial island, it seems very likely that the signal(s) originated from the astroglial cell on which it resided. The interesting case comes when physical contact is limited, when a neuron straddles an astroglial cell, such that part of the growing arbor touches and part does not (Figure 3). When in partial contact, the dendritic arbor forms asymmetrically, with the most extensive arborization not in direct contact. One interpretation of this biased growth is that it is the product of an interplay between the action of soluble factors produced by astroglia and a separate inhibition of growth when dendrites are in direct contact with the surface of astroglial cells.
4. If astrocytes sculpt dendrites in vitro , might they also influence dendrite arbor shape in vivo ?
The effects of physical contact between a dendritic branch and astroglia
The arbors of pyramidal neurons in hippocampal subfield CA1 offer a useful model because this population of cells has elaborate arbors, yet the arrangement of arbor branches repeats with striking regularity (see Figure 4B). The story of how this pattern of arborization arises in development is summarized nicely by Pokorny and Yamamoto [35]. In that report, dendrite branching and elongation, as measured in Golgi-impregnated pyramidal cells, was not synchronous but rather followed a distinct sequence. For example, the apical dendrite extended nearly to its mature length by postnatal day (P)10, but the lateral branches along the apical shaft had only extended a minor fraction of their mature length. There was also a temporal separation when these lateral branches formed. The number of lateral branches that arose from the apical shaft within the proximal stratum radiatum peaked at P15, whereas more distally, the number continued to be added out to P48. These zones within stratum radiatum correspond to afferent inputs from associative and commissural fibers (proximal stratum radiatum) and Schaffer collaterals (distal stratum radiatum). Branching within stratum lacunosum-moleculare, originating from the most distal portions of the apical dendrite, did not peak until after P48 and appeared to be more pronounced in the preterminal branches. The availability of afferents, which enter during embryonic development (for a review, see [65]), could be an important source of cues for dendritic development.
During the time frame when CA1 pyramidal cells are growing dendrites, astroglial cells in this region go through a number of transitions in number, and structure, that could be meaningful for establishing arbor pattern. Though relatively sparse before P10, astrocytes are present at the time when the apical dendrite is forming, and during the first 2 weeks of postnatal development, astroglia extend long filopodia-like processes [66]. An intriguing possibility is that during early stages of dendritic branch formation, the long filopodial extensions on glia serve a function related to branch formation or guidance, analogous to the guidance processes extended by radial glial cells. By the time astroglia begin to extend elaborate spongiform processes more characteristic of mature astroglia, the architecture of the arbor has been established, although branch growth continues beyond P30, when astrocytes have established nonoverlapping territories characteristic of mature neuropil [66].
Striking changes in the shape or spatial orientation of astroglia also accompany the most active periods of dendritic branch formation and growth. Astroglia are initially spherical but take on a polarized shape with development [66, 67]. In the stratum radiatum, this shape change is oriented perpendicularly to the cell body layer, stratum pyramidale. In the stratum lacunosum-moleculare, the astroglia are elongated parallel to the cell body layer [67]. Coincidentally, this is the zone of the apical dendritic arbor that shows the most prominent lateral spread.
Comparison of dendritic arbors of neurons and arrangement of astrocytic processes in neuropil suggests that the structures of these two cell types co-vary in a nonrandom manner (see Figure 4). Such a view, however, only begins to represent more nuanced phenotypic heterogeneity of astroglia based on patterns of gene expression that are of emerging importance in current research, for review, see [73]. Likewise, these kinds of analyses only begin to disclose the developmental shifts in phenotype of astrocytes across lamina that may accompany distinct stages of dendritic branch formation. Such shifts appear to occur. As early as P8, GFAP-positive astroglia are densely arranged in the stratum lacunosum-moleculare, while remaining comparatively sparse in the stratum radiatum [67]. Additionally, two different transporters for glutamate show a different time course of expression and distinctive localization in different populations of astroglia in the developing hippocampus [48]. While such complexities are far from resolved, there is enough data available, we argue, to make the case that (1) patterning of dendritic branches is subject to the influence of astroglia and that (2) this relatively neglected developmental effect is distinct from the actively studied influences on synapse formation. The purpose of this chapter was to build on the hypothesis proposed by Procko and Shaham [8] by adding supporting evidence based on direct analysis of dendritic arbor formation in principle neurons of the central nervous system. Both the documented impact of astrocytes on dendritic arbor formation
Acknowledgments
This work was supported by funding from NIH 1R15HD061831 and NSF DBI-1039958 and a generous gift to Whitman College from the family of Dr. Robert F. Welty. We thank the many undergraduate students who have contributed to the research findings described here and NoahLani Litwinsella for the artwork in Figure 5.
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