Astrocytes refine cortical connectivity at dendritic spines

Abstract

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.DOI: http://dx.doi.org/10.7554/eLife.04047.001

Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila

“…For example, in the antennal lobe of Drosophila the morphology and connectivity of local interneurons can vary between animals and may require NG to respond accordingly (Chou et al, 2010). Finally, NG may also play an important role in maintaining axons and in monitoring and pruning synapses to ensure the proper number and type of synaptic connections, as they do in invertebrates (O’Connor et al, 2017) and vertebrates (Risher et al, 2014), respectively, during normal development and after injury (Burda et al, 2016; He and Jin, 2016; Stephan et al, 2012). Glial developmental plasticity may be essential to achieve robustness and maintain homeostasis by readily adapting to these and perhaps other variations in nervous system size and morphology.…”

Cell Biology of Astrocyte-Synapse Interactions

“…This has been shown to be the case for Hevin. In the developing mouse cortex, Hevin is specifically required for the formation of a subset of excitatory synapses: the thalamocortical connections between thalamic axons and cortical dendrites (Risher et al, 2014). Investigation of the ultrastructure of cortical dendrites at high resolution revealed that astrocyte-secreted Hevin is required for a developmental refinement step that occurs at the level of single dendritic spine heads.…”

“…As synapses mature the spines lose one of these inputs and keep the other, achieving the characteristic “one spine = one synapse” organization. Absence of Hevin results in persistence of dendritic spines which are still doubly innervated, most likely due to the inability of thalamocortical connections to compete for spines with cortical inputs (Risher et al, 2014). …”

“…First, many astrocyte synaptogenic signals show temporal differences in mRNA and protein expression levels. For example in the cortex, thrombospondins 1 and 2 are most highly expressed in the first postnatal week when synapses are first forming and downregulated after that, whereas Hevin increases in the second postnatal week when synapses are maturing (Cahoy et al, 2008; Christopherson et al, 2005; Risher et al, 2014). It is not known whether these changes in expression of synaptogenic factors are an intrinsic part of the astrocyte maturation process, or being regulated by interactions with neighboring neurons.…”

“Targeting astrocytes in CNS injury and disease: A translational research approach”

“…Astrocytes have been found to be important in presynaptic muting of hippocampal neurons, again through their expression of thrombospondins (Crawford et al, 2012). Another astrocyte-secreted protein, hevin, has been implicated in regulating cortical connectivity during development by refining dendritic spines (Risher et al, 2014). They also play a role in targeting synapses for elimination (Stevens et al, 2007).…”