Abstract
BackgroundActivation of G protein coupled receptor (GPCR) in astrocytes leads to Ca2+-dependent glutamate release via Bestrophin 1 (Best1) channel. Whether receptor-mediated glutamate release from astrocytes can regulate synaptic plasticity remains to be fully understood.ResultsWe show here that Best1-mediated astrocytic glutamate activates the synaptic N-methyl-D-aspartate receptor (NMDAR) and modulates NMDAR-dependent synaptic plasticity. Our data show that activation of the protease-activated receptor 1 (PAR1) in hippocampal CA1 astrocytes elevates the glutamate concentration at Schaffer collateral-CA1 (SC-CA1) synapses, resulting in activation of GluN2A-containing NMDARs and NMDAR-dependent potentiation of synaptic responses. Furthermore, the threshold for inducing NMDAR-dependent long-term potentiation (LTP) is lowered when astrocytic glutamate release accompanied LTP induction, suggesting that astrocytic glutamate is significant in modulating synaptic plasticity.ConclusionsOur results provide direct evidence for the physiological importance of channel-mediated astrocytic glutamate in modulating neural circuit functions.
Highlights
Activation of G protein coupled receptor (GPCR) in astrocytes leads to Ca2+-dependent glutamate release via Bestrophin 1 (Best1) channel
Immunostaining analysis using protease-activated receptor 1 (PAR1)-specific antibody showed that endogenous PAR1 is selectively expressed in astrocytes, because ~90% of GFAP-positive astrocytes showed PAR1 expression (90.0 ± 4.9%, n = 4), whereas there was no significant expression in neuronal cells, as shown in previous studies in human and rat brain (Figure 1A,B) [20,22]
We found that bath application of the PAR1 agonist, TFLLR-NH2 peptide agonist (TFLLR) (30 μM) [8,20,26] increases extracellular glutamate level around a single CA1 astrocyte, and that this elevation of extracellular glutamate level was significantly reduced in slices of Best1 knockout mice (Best1 KO : Figure 1F,G)
Summary
Activation of G protein coupled receptor (GPCR) in astrocytes leads to Ca2+-dependent glutamate release via Bestrophin 1 (Best1) channel. Whether receptor-mediated glutamate release from astrocytes can regulate synaptic plasticity remains to be fully understood. Astrocytically released glutamate has been suggested to play a crucial role in mediating neuronal-glial circuits. Park et al Molecular Brain (2015) 8:7 glutamate in synaptic functions, we have searched for an effective and reliable tool for triggering glutamate release from astrocytes. Mounting evidence supports the ability of PAR1 to trigger the Ca2+-dependent signaling pathways crucial for astrocytic glutamate release. PAR1 activation was shown to be effective for triggering Ca2+-dependent astrocytic glutamate release when compared with the activation by other GPCRs [14,21]. PAR1 appears to be a useful tool for selective induction of Ca2+-dependent glutamate release from astrocytes in vitro and in vivo [10,11,14,20,23,24,25,26]
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