Glutamate Released from Glial Cells Synchronizes Neuronal Activity in the Hippocampus

Abstract

Glial cells of the nervous system directly influence neuronal and synaptic activities by releasing transmitters. However, the physiological consequences of this glial transmitter release on brain information processing remain poorly understood. We demonstrate here in hippocampal slices of 2-to 5-week-old rats that glutamate released from glial cells generates slow transient currents (STCs) mediated by the activation of NMDA receptors in pyramidal cells. STCs persist in the absence of neuronal and synaptic activity, indicating a nonsynaptic origin of the source of glutamate. Indeed, STCs occur spontaneously but can also be induced by pharmacological tools known to activate astrocytes and by the selective mechanical stimulation of single nearby glial cells. Bath application of the inhibitor of the glutamate uptake DL-threo-␤-benzyloxyaspartate increases both the frequency of STCs and the amplitude of a tonic conductance mediated by NMDA receptors and probably also originated from glial glutamate release. By using dual recordings, we observed synchronized STCs in pyramidal cells having their soma distant by Ͻ100 m. The degree of precision (Ͻ100 msec) of this synchronization rules out the involvement of calcium waves spreading through the glial network. It also indicates that single glial cells release glutamate onto adjacent neuronal processes, thereby controlling simultaneously the excitability of several neighboring pyramidal cells. In conclusion, our results show that the glial glutamate release occurs spontaneously and synchronizes the neuronal activity in the hippocampus.

Enhanced Astrocytic Ca2+Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus

“…and CA3 of the hippocampus (Angulo et al, 2004;Fellin et al, 2004;Kang et al, 2005;Perea and Araque, 2005;Tian et al, 2005), the thalamus (Parri et al, 2001), the olfactory bulb (Kozlov et al, 2006), the nucleus accumbens (D'Ascenzo et al, 2007), and the cortex (this study), it is likely that they are a general property of the nervous system.…”

“…mGluR5-dependent activation of astrocytic Ca 2؉ signaling evokes NR2B-dependent NMDA receptor-mediated neuronal currents Because of the potential for astrocytic Ca 2ϩ signals to cause glutamatemediated neuronal excitation, as has been described for thalamic (Parri et al, 2001), hippocampal pyramidal neurons (Angulo et al, 2004;Fellin et al, 2004;Kang et al, 2005;Perea and Araque, 2005), and medium spiny neurons of the nucleus accumbens (D'Ascenzo et al, 2007), we performed studies in acutely isolated brain slices to determine whether layer 2/3 cortical astrocytes excite cortical pyramidal neurons. Astrocytic Ca 2ϩ signals evoked SICs mediated by NMDA receptors that can be identified based on four properties (Parri et al, 2001;Angulo et al, 2004;Fellin et al, 2004;Perea and Araque, 2005): their slow kinetics, their insensitivity to TTX and 2,3-dioxo -6 -nitro -1,2,3,4 -tetrahydrobenzoquinoxaline -7 -sulfonamide (NBQX), and their blockade by D-AP5. The class I mGluR agonist DHPG (10 -20 M) as well as the mGluR5 selective agonist CHPG (0.5-1 mM) induced TTX-insensitive SICs in layer 2/3 cortical neurons that were blocked by the mGluR5 antagonist MPEP (50 M) (Fig.…”

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

“…NMDARs are mostly postsynaptic in the hippocampus (Nyiri et al, 2003;Takumi et al, 1999), and have a greater expression of NR2B subunits than other NMDA subunits (ie, NR2A) in the CA1 subregion, but not in the CA3 subregion or the dentate gyrus (Coultrap et al, 2005;Pandis et al, 2006). Also, within the CA1 subregion, NMDAR subunit composition and density vary across cell types (Angulo et al, 2004;Nyiri et al, 2003;Serrano et al, 2006;Serrano et al, 2008;Siegel et al, 1994;Szabadits et al, 2011;Todd et al, 2006;Xue et al, 2011). Thus, given the functional heterogeneity of hippocampal NMDAR populations (Kesner, 2007;Lee et al, 2003), future studies will be necessary to dissect the role of distinct NR2B subunitcontaining NMDAR subpopulations within the DH in drug context-induced cocaine-seeking behavior.…”

Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis

“…Later studies demonstrated that this process can be observed in acute brain slices[71,72,73,74,75,76,77,78,79] and in vivo [80]. Astrocytes were later shown to release a number of chemical transmitters, including ATP[81,82,83,84,85], D-serine[86,87,88,89], TNF-alpha[90,91], and ANP[92], in a process that has recently been termed gliotransmission[93].…”