Direct Astrocytic Contacts Regulate Local Maturation of Dendritic Spines

Abstract

Astrocytes contribute on both development and function of synapses, but it remains unclear whether direct astrocytic contacts regulate development of individual synapses. Two-photon time-lapse imaging of astrocytic and dendritic protrusive activity revealed the correlation of astrocytic contacts with both lifetime and morphological maturation of dendritic protrusions. Astrocytic motility was essential in maturation of spines, because its suppression by manipulating Rac1-dependent signaling in astrocytes resulted in induction of longer, filopodia-like dendritic protrusions. Manipulation of ephrin/Eph-dependent neuron–astrocyte signaling suggested involvement of this signaling pathway in astrocyte-dependent stabilization of newly generated dendritic protrusions. Our data support a model in which astrocytic protrusive activity in development acts as a key local regulator for stabilization of individual dendritic protrusions and subsequent maturation into spines.

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…Structural changes in astroglial filopodia‐like protrusions can be routinely observed using time‐lapse light microscopy in cultured hippocampal or cortical astrocytes (Cornell‐Bell et al, 1990a; Lavialle et al, 2011; Molotkov et al, 2013). In acute brain slices some mobile astrocytic processes can be detected (Hirrlinger et al, 2004; Nishida and Okabe, 2007; Nixdorf‐Bergweiler et al, 1994). Very fine, and apparently highly mobile, astrocytic processes have been reported in organotypic brain slices using a membrane‐bound GFP (Benediktsson et al, 2005).…”

“…In cultures (Safavi‐Abbasi et al, 2001) as well as slices (Lippman et al, 2008; Nestor et al, 2007; Nishida and Okabe, 2007) astrocytic processes can adapt quickly to changes in their environment through a mechanism involving the GTPase Rac‐1. Moreover, expression of a dominant negative form of the actin‐binding protein profilin‐1 inhibited filopodia formation and motility (Molotkov et al, 2013).…”

“…This receptor tyrosine kinase is located in dendritic spines, and its ligand ephrin‐A3 is enriched in PAP membranes (Murai et al, 2003). Binding of the two molecules is important for normal spine morphology (Murai et al, 2003) and mitigating the contact leads to unstable spines (Nishida and Okabe, 2007). Furthermore, the binding of exogenous and endogenous ephrin‐A to astrocytic EphA ligands mediates astrocyte process outgrowth (Nestor et al, 2007).…”

“…In hippocampal slices, spines disappear more frequently when PAPs are not present (Nishida and Okabe, 2007). The same effect was found when ephrin signaling was perturbed, and dendritic protrusions disappeared faster, although they were in contact with astrocytic processes (Nishida and Okabe, 2007). Furthermore, blocking Rac‐1 and interfering with PAP motility leads to enhanced number of dendritic filopodia (Nishida and Okabe, 2007).…”

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

“…At one extreme, cerebellar synapses formed by climbing fibers in rodents show an average degree of enwrapping around 87% (Xu-Friedman et al, 2001), whereas estimates of degree of enwrapping in the neocortex are lower and suggest that ensheathment is rare (<10% of synapses), and contact with the dendritic spine (but not the axon-spine interfaces) dominates (70%) (Genoud et al, 2006). The significance of these differences is poorly understood, but may involve 1) the stability and maturity of the synapse (Nishida and Okabe, 2007;Medvedev et al, 2014), 2) patterns of neuronal connectivity, such that some areas are by design more disposed to transmitter spillover (Bernardinelli et al, 2014), and 3) dynamic astrocytic process extension and retraction in response to neuronal activity and hormonal changes (Theodosis et al, 2008). These distances, however, should be viewed as relative, since these methods do not account for the actual diffusion pathway, which is tortuous, and all measurements taken from chemically-fixed EM preparations are subject to non-uniform shrinkage, making astrocytes appear to be located closer to synapses than they are in vivo (Korogod et al, 2015).…”