Selective Stimulation of Astrocyte Calcium In Situ Does Not Affect Neuronal Excitatory Synaptic Activity

Abstract

Astrocytes are considered the third component of the synapse, responding to neurotransmitter release from synaptic terminals and releasing gliotransmitters--including glutamate--in a Ca(2+)-dependent manner to affect neuronal synaptic activity. Many studies reporting astrocyte-driven neuronal activity have evoked astrocyte Ca(2+) increases by application of endogenous ligands that directly activate neuronal receptors, making astrocyte contribution to neuronal effect(s) difficult to determine. We have made transgenic mice that express a Gq-coupled receptor only in astrocytes to evoke astrocyte Ca(2+) increases using an agonist that does not bind endogenous receptors in brain. By recording from CA1 pyramidal cells in acute hippocampal slices from these mice, we demonstrate that widespread Ca(2+) elevations in 80%-90% of stratum radiatum astrocytes do not increase neuronal Ca(2+), produce neuronal slow inward currents, or affect excitatory synaptic activity. Our findings call into question the developing consensus that Ca(2+)-dependent glutamate release by astrocytes directly affects neuronal synaptic activity in situ.

Loss of IP3Receptor-Dependent Ca2+Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity

“…The IP 3 R2 KO mouse model offers a compliment to another mouse model developed in our laboratory that enables selective stimulation of G q -GPCR signaling cascades in astrocytes (Fiacco et al, 2007). The findings presented here support our recent discovery using the MrgA1 transgenic mice that selective, widespread astrocyte Ca 2ϩ elevations have no effect on baseline neuronal excitatory synaptic activity.…”

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…This does not necessarily imply that elegant experimental manipulations with astroglial Ca 2+ within a certain dynamic range by triggering certain cellular cascades should reproduce such effects (Agulhon et al, 2010; Fiacco et al, 2007; Petravicz et al, 2008) (see (Rusakov et al, 2014; Volterra et al, 2014) for discussion). In addition to the much debated astrocyte‐neuron exchange, Ca 2+ rises in astrocytes could also boost the expression level of glutamate transporters (Devaraju et al, 2013), re‐position mitochondria closer to glutamate transporters (Jackson et al, 2014; Ugbode et al, 2014), and regulate neuro‐metabolic coupling with neurons (Bernardinelli et al, 2004; Porras et al, 2008).…”

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

“…Also, BAPTA-loaded astrocytes showed a significantly lower PAP motility than control astrocytes (Figure 2A), suggesting that PAP motility is regulated through Ca 2+ . We then selectively induced Ca 2+ transients in astrocytes using the astrocyte-specific expression of exogenous Gq-coupled receptors of the Mas-related gene family (MrgA1 and MrgC11 [34,35]; Figure 2D) combined with the bath application of the MrgA1 agonist peptide Phe-Met-Arg-Phe-NH 2 (FMRFa) [34]. This induced both Ca 2+ i transients ( Figures 2E and 2F) and an increase in PAP motility in the infected astrocytes ( Figure 3G).…”