Glutamate release from astrocytes as a non-synaptic mechanism for neuronal synchronization in the hippocampus

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Abstract

Synchronization of activity of anatomically distributed groups of neurons represents a fundamental event in the processing of information in the brain. While this phenomenon is believed to result from dynamic interactions within the neuronal circuitry, how exactly populations of neurons become synchronized remains largely to be clarified. We propose that astrocytes are directly involved in the generation of neuronal synchrony in the hippocampus. By using a combination of experimental approaches in hippocampal slice preparations, including patch–clamp recordings and confocal microscopy calcium imaging, we studied the effect on CA1 pyramidal neurons of glutamate released from astrocytes upon various stimuli that trigger Ca2+ elevations in these glial cells, including Schaffer collateral stimulation. We found that astrocytic glutamate evokes synchronous, slow inward currents (SICs) and Ca2+ elevations in CA1 pyramidal neurons by acting preferentially, if not exclusively, on extrasynaptic NMDA receptors. Due to desensitization, AMPA receptors were not activated by astrocytic glutamate unless cyclothiazide was present. In the virtual absence of extracellular Mg2+, glutamate released from astrocytes was found to evoke, in paired recordings, highly synchronous SICs from two CA1 pyramidal neurons and, in Ca2+ imaging experiments, Ca2+ elevations that occurred synchronously in domains composed of 2–12 CA1 neurons. In the presence of extracellular Mg2+ (1 mM), synchronous SICs in two neurons as well as synchronous Ca2+ elevations in neuronal domains were still observed, although with a reduced frequency. Our results reveal a functional link between astrocytic glutamate and extrasynaptic NMDA receptors that contributes to the overall dynamics of neuronal synchrony. Our observations also raise a series of questions on possible roles of this astrocyte-to-neuron signaling in pathological changes in the hippocampus such as excitotoxic neuronal damage or the generation of epileptiform activity.

Introduction

The neuron is traditionally viewed as the functional unit of the nervous system. The brain can thus be regarded as an ensemble of excitatory and inhibitory neurons that are connected dynamically at the synapse. Accordingly, synaptic transmission in the neural network is considered to play a unique, fundamental role in information processing. Recently, however, astrocyte-to-neuron communication has emerged as a novel signalling pathway that uses the same transmitters that mediate the transfer of information between neurons at the synapse (Araque et al., 1999, Carmignoto, 2000, Haydon, 2001, Newman, 2003b, Volterra and Meldolesi, 2005). It has thus been proposed that neurons and astrocytes represent a distinct multifunctional unit in the brain (Fellin and Carmignoto, 2004).

Among the various neuroactive compounds that astrocytes use to signal to neurons, ATP (Coco et al., 2003, Guthrie et al., 1999, Newman, 2003a, Queiroz et al., 1999, Zhang et al., 2003) and the excitatory aminoacid glutamate (Araque et al., 1998, Bezzi et al., 1998, Parpura et al., 1994, Pasti et al., 2001) are certainly the most widely studied. This short review will focus on the most recent findings that provide insights into the functional role that can be ascribed to glutamate of astrocytic origin in the neural network.

Section snippets

Astrocytes signal to neurons at extrasynaptic sites

Astrocyte processes contact a large proportion of the synapses in the hippocampus (Ventura and Harris, 1999). This spatial proximity is functional to a series of important tasks that astrocytes exploit to assist neurons, such as the buffering of extracellular potassium and the uptake (and recycling) of the neurotransmitter glutamate in the vicinity of the synaptic cleft (Bergles et al., 1997, Bergles and Jahr, 1998). However, when dealing with the ability of astrocytic glutamate to activate

Astrocytic glutamate-mediated neuronal synchrony

Pair recording experiments revealed that astrocytic glutamate can activate SICs in the two recorded neurons with a high degree of temporal correlation (Angulo et al., 2004, Fellin et al., 2004). Such a synchronization cannot derive from spreading of the current through gap junctions since depolarizing voltage pulses applied to each neuron of the pair always failed to reveal evidence of electrical coupling between neurons which display synchronized responses (Fellin et al., 2004). Neuronal

Acknowledgements

This work was supported by grants from the Armenise–Harvard University Foundation and the Italian University and Health Ministries to G.C. (FIRB, RBNE01RHZM_003).

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