Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity

Abstract

Astrocytes exhibit spontaneous calcium oscillations that could induce the release of glutamate as gliotransmitter in rat hippocampal slices. However, it is unknown whether this spontaneous release of astrocytic glutamate may contribute to determining the basal neurotransmitter release probability in central synapses. Using whole-cell recordings and Ca(2+) imaging, we investigated the effects of the spontaneous astrocytic activity on neurotransmission and synaptic plasticity at CA3-CA1 hippocampal synapses. We show here that the metabolic gliotoxin fluorocitrate (FC) reduces the amplitude of evoked excitatory postsynaptic currents and increases the paired-pulse facilitation, mainly due to the reduction of the neurotransmitter release probability and the synaptic potency. FC also decreased intracellular Ca(2+) signalling and Ca(2+) -dependent glutamate release from astrocytes. The addition of glutamine rescued the effects of FC over the synaptic potency; however, the probability of neurotransmitter release remained diminished. The blockage of group I metabotropic glutamate receptors mimicked the effects of FC on the frequency of miniature synaptic responses. In the presence of FC, the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N ',N '-tetra-acetate or group I metabotropic glutamate receptor antagonists, the excitatory postsynaptic current potentiation induced by the spike-timing-dependent plasticity protocol was blocked, and it was rescued by delivering a stronger spike-timing-dependent plasticity protocol. Taken together, these results suggest that spontaneous glutamate release from astrocytes contributes to setting the basal probability of neurotransmitter release via metabotropic glutamate receptor activation, which could be operating as a gain control mechanism that regulates the threshold of long-term potentiation. Therefore, endogenous astrocyte activity provides a novel non-neuronal mechanism that could be critical for transferring information in the central nervous system.

Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond

“…First, one might see excessive stimulation of perisynaptic and extrasynaptic metabotropic glutamate receptors (mGluRs). Overstimulation of presynaptic mGluR2 receptors has been shown to depress glutamate neurotransmission and compromise synaptic connectivity (99), consistent with the association of elevated anterior cingulate glutamate levels and reduced cingulate functional connectivity in major depression (100). Stress induced glutamate release also may enhance an NMDA/AMPA bias in signaling as stimulation of postsynaptic group I mGluRs enhances NMDA receptor signaling promotes long-term depression and internalization of AMPA receptors (101).…”

Neuron-glia networks: integral gear of brain function

“…For example, a single gliotransmitter may exert multiple effects on the neuronal network depending on the receptor subtype and its subcellular membrane location. Indeed, glutamate released by astrocytes increases neuronal excitability by inducing slow inward currents (SICs) in excitatory neurons through activation of postsynaptic NMDA receptors (Parri et al, 2001; Angulo et al, 2004; Fellin et al, 2004; Perea and Araque, 2005; Navarrete and Araque, 2008; Shigetomi et al, 2008; Chen et al, 2012); but it also enhances synaptic transmission through activation of presynaptic metabotropic glutamate receptors (mGluRs) group I (Fiacco and McCarthy, 2004; Perea and Araque, 2007; Navarrete and Araque, 2010; Bonansco et al, 2011; Perea et al, 2014); and stimulates synaptic transmission by activation of presynaptic NMDA receptors in dentate granule cells (Jourdain et al, 2007). In addition, astrocytes release different gliotransmitters with different neuromodulatory effects.…”

Astrocyte–Neuron Communication: Functional Consequences

“…SICs trigger the synchronicity of neuronal activity [31,32] but their exact function and importance in the hippocampus is still unknown, and even questioned by some [21]. On the other hand mGluR5 receptor activation by astrocytes affects the release probability of the presynaptic terminals and consequently participates in synaptic plasticity [33,34]. Recently, experiments performed in vivo indicated that sensory stimulation and stimulations of the medial septal induced LTP at CA3-CA1 synapses [35].…”