Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

Abstract

SummaryBackground: Excitatory synapses in the CNS are highly dynamic structures that can show activity-dependent remodeling and stabilization in response to learning and memory. Synapses are enveloped with intricate processes of astrocytes known as perisynaptic astrocytic processes (PAPs). PAPs are motile structures displaying rapid actin-dependent movements and are characterized by Ca 2+ elevations in response to neuronal activity. Despite a debated implication in synaptic plasticity, the role of both Ca 2+ events in astrocytes and PAP morphological dynamics remain unclear. Results: In the hippocampus, we found that PAPs show extensive structural plasticity that is regulated by synaptic activity through astrocytic metabotropic glutamate receptors and intracellular calcium signaling. Synaptic activation that induces long-term potentiation caused a transient PAP motility increase leading to an enhanced astrocytic coverage of the synapse. Selective activation of calcium signals in individual PAPs using exogenous metabotropic receptor expression and two-photon uncaging reproduced these effects and enhanced spine stability. In vivo imaging in the somatosensory cortex of adult mice revealed that increased neuronal activity through whisker stimulation similarly elevates PAP movement. This in vivo PAP motility correlated with spine coverage and was predictive of spine stability. Conclusions: This study identifies a novel bidirectional interaction between synapses and astrocytes, in which synaptic activity and synaptic potentiation regulate PAP structural plasticity, which in turn determines the fate of the synapse. This mechanism may represent an important contribution of astrocytes to learning and memory processes.

Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain

“…Astrocytes respond to sensory inputs or synaptic activity with intracellular Ca 2+ rises and remodeling of perisynaptic astrocytic processes, resulting in the release of neuroactive substances that may not only acutely affect synaptic and neuronal activity, but may also result in slower and more chronic aspects of neuronal plasticity (23,(51)(52)(53)(54)(55). Indeed, slower astrocyte-neuron interaction is more consistent with the temporal dynamics of astrocytic Ca 2+ waves, which are much slower than the rapid time course of synaptic transmission (53).…”

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…Very fine, and apparently highly mobile, astrocytic processes have been reported in organotypic brain slices using a membrane‐bound GFP (Benediktsson et al, 2005). Furthermore, co‐labeling of dendritic spines and PAPs in hippocampal (Halassa et al, 2007a; Perez‐Alvarez et al, 2014; Verbich et al, 2012) and cerebellar slices (Lippman Bell et al, 2010; Lippman et al, 2008) as well as in vivo (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014) suggested that PAPs are highly dynamic structures that engage and disengage with dendritic spines, also responding to the induction of synaptic plasticity (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014). …”

“…Astrocytes (and probably PAPs) express both, AMPARs and mGluRs (see above) and both receptor types might be involved in astrocytic filopodia outgrowth (Bernardinelli et al, 2014a). More recently, the induction of LTP in hippocampal slices and whisker stimulation has led to measureable PAP displacement in the hippocampus and the barrel cortex, respectively (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014). It was suggested that PAP motility is (a) synapse‐specific, (b) neuronal activity‐dependent (application of TTX blocks PAP movement), (c) mGluR‐dependent, (d) Ca 2+ ‐dependent, and (e) IP 3 ‐dependent (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014).…”

“…More recently, the induction of LTP in hippocampal slices and whisker stimulation has led to measureable PAP displacement in the hippocampus and the barrel cortex, respectively (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014). It was suggested that PAP motility is (a) synapse‐specific, (b) neuronal activity‐dependent (application of TTX blocks PAP movement), (c) mGluR‐dependent, (d) Ca 2+ ‐dependent, and (e) IP 3 ‐dependent (Bernardinelli et al, 2014b; Perez‐Alvarez et al, 2014). These observations raise an intriguing question of whether there are organizational principles for the presence and shape of PAPs depending on the brain area, synaptic types and species (Reichenbach et al, 2010).…”

Intravital imaging of dendritic spine plasticity

“…A recent study showed that the motility of perisynaptic astrocytic processes that enveloped dendritic spines correlated with spine coverage and promoted spine stability in the mouse somatosensory cortex after whisker stimulation. 61 Another study showed that a blockade of astrocytic glutamate uptake accelerated experience-dependent spine elimination during development. 62 Microglia has also been found to closely interact with spines.…”