Astrocytic group I mGluR-dependent potentiation of astrocytic glutamate and potassium uptake

Abstract

One of the most important functions of astrocytes is removal of glutamate released during synaptic transmission. Surprisingly, the mechanisms by which astrocyte glutamate uptake is acutely modulated remain to be clarified. Astrocytes express metabotropic glutamate receptors (mGluRs) and other G protein-coupled receptors (GPCRs), which are activated during neuronal activity. Here, we test the hypothesis that astrocytic group I mGluRs acutely regulate glutamate uptake by astrocytes in situ. This hypothesis was tested in acute mouse hippocampal slices. Activation of astrocytic mGluRs, using a tetanic high-frequency stimulus (HFS) applied to Schaffer collaterals, led to potentiation of the amplitude of the synaptically evoked glutamate transporter currents (STCs) and associated charge transfer without changes in kinetics. Similar potentiation of STCs was not observed in the presence of group I mGluR antagonists or the PKC inhibitor, PKC 19-36, suggesting that HFS-induced potentiation of astrocyte glutamate uptake is astrocytic group I mGluR and PKC dependent. Pharmacological stimulation of a transgenic GPCR (MrgA1R), expressed exclusively in astrocytes, also potentiated STC amplitude and charge transfer, albeit quicker and shorter lasting compared with HFS-induced potentiation. The amplitude of the slow, inward astrocytic current due to potassium (K(+)) influx was also enhanced following activation of the endogenous mGluRs or the astrocyte-specific MrgA1 Gq GPCRs. Taken together, these findings suggest that astrocytic group I mGluR activation has a synergistic, modulatory effect on the uptake of glutamate and K(+).

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

“…This is likely to occur at individual synapses, as LTP-induced PAP motility selectively modified the structural organization and spine coverage around potentiated synapses, which in turn was associated with an increased stability of synapses. Thus, in addition to regulating glutamate transport [40], the release of gliotransmitters [41], and neurometabolic coupling [42], astrocytic Ca 2+ dynamics are important to regulate PAP motility and thereby the stability of the tripartite synapse. These results provide a new mechanism through which synaptic activation can control the physical interactions between PAPs and excitatory synapses, and they demonstrate an important structural role of PAPs as active partners in the regulation of activity-dependent synaptic remodeling.…”

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). Recent findings suggest that such Ca 2+ signals could be required for morphological changes in PAPs (Molotkov et al, 2013; Tanaka et al, 2013).…”

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

“…Four sweeps of GTCs were averaged and the mean amplitude and charge transfer of GTCs were measured. 14,37 The commercial computer software Clampfit (Molecular Device, Sunnyvale, CA) was used for data analysis.…”