Glial glutamate transport modulates dendritic spine head protrusions in the hippocampus

Abstract

Accumulating evidence supports the idea that synapses are tripartite, whereby perisynaptic astrocytes modulate both pre- and postsynaptic function. Although some of these features have been uncovered by using electrophysiological methods, less is known about the structural interplay between synapses and glial processes. Here, we investigated how astrocytes govern the plasticity of individual hippocampal dendritic spines. Recently, we uncovered that a subgroup of innervated dendritic spines is able to undergo remodeling by extending spine head protrusions (SHPs) toward neighboring functional presynaptic boutons, resulting in new synapses. Although glutamate serves as a trigger, how this behavior is regulated is unknown. As astrocytes control extracellular glutamate levels through their high-affinity uptake transporters, together with their privileged access to synapses, we investigated a role for astrocytes in SHP formation. Using time-lapse confocal microscopy, we found that the volume overlap between spines and astrocytic processes decreased during the formation of SHPs. Focal application of glutamate also reduced spine-astrocyte overlap and induced SHPs. Importantly, SHP formation was prevented by blocking glial glutamate transporters, suggesting that glial control of extracellular glutamate is important for SHP-mediated plasticity of spines. Hence, the dynamic changes of both spines and astrocytes can rapidly modify synaptic connectivity.

Emerging roles of astrocytes in neural circuit development

“…Therefore, remodelling of astrocytic processes is likely to have a large influence on the glutamate concentration at the synaptic cleft and the size of the postsynaptic current. ‘Spillover’ of glutamate into the local area around the synapse has been reported to direct the remodelling of dendritic spines and to promote the extension of new spine heads towards neighbouring presynaptic terminals, resulting in the formation of new synapses 68 . Interestingly, astrocytes were found to reduce their contact with spines during spine head remodelling 68 .…”

“…‘Spillover’ of glutamate into the local area around the synapse has been reported to direct the remodelling of dendritic spines and to promote the extension of new spine heads towards neighbouring presynaptic terminals, resulting in the formation of new synapses 68 . Interestingly, astrocytes were found to reduce their contact with spines during spine head remodelling 68 . In addition, spine head remodelling was inhibited by glutamate transporter blockers, suggesting that glial control of extracellular glutamate is important for plastic changes in spine morphology 68 .…”

Laminar and subcellular heterogeneity of GLAST and GLT‐1 immunoreactivity in the developing postnatal mouse hippocampus

“…Such a coincidental progression has already been described for other brain regions by Furuta and co-workers (1997). Indeed, glutamate uptake through GLT-1 is an important functional element of mature hippocampal synapses (Arnth-Jensen et al, 2002;Verbich et al, 2012), and it was recently shown that GLT-1 protein upregulation during postnatal development is correlated to the frequency of transmitter release at excitatory synaptic sites (Benediktsson et al, 2012).…”

“…On the other hand side, GLT-1 is vital for synapse establishment (Benediktsson et al, 2012;Verbich et al, 2012). The close interrelationship and the functional importance of this transporter for synaptic function is also evident from its prominent perisynaptic localization, which has been established by several groups using both electron microscopy and light microscopic techniques (e.g., Chaudry et al, 1995;Minelli et al, 2001;Cholet et al, 2002;Benediktsson et al, 2012).…”

Perisynaptic astroglial processes: dynamic processors of neuronal information

“…Mechanisms behind these morphological changes involve release of glutamate from axon terminals, acting as a signal for both dendritic spines and PAPs (Hirrlinger et al 2004;Haber et al 2006). Interestingly, dendritic remodeling mediated by glutamate spillover occurring in the hippocampus (Verbich et al 2012) is associated with an adjustment of astrocytic process morphology, weakening PAP association with spines, and hence dynamically reducing GluT activity. PAP-spine association is also regulated through activation of dendritic EphA4 receptors with the astrocytic ligand ephrinA3, which results in spine retraction and reduces the lifetime of newly generated dendrites (Murai et al 2003;Nishida and Okabe 2007).…”