Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

Gertrudis Perea,Sara Mederos,Amit Agarwal,Alfonso Araque,Laura Schlosser,Mario Martín-Fernández,Adolfo Díez,Abdelrahman Rayan,Denise Manahan-Vaughan,Ana Covelo,Ruth Quintana,Ricardo Gómez,Eduardo D Martín,Bernhard Bettler,Dwight E Bergles,Jesús J Ballesteros,Frank Kirchhoff,Marco Fuenzalida,Alicia Hernández-Vivanco

doi:10.7554/elife.20362

Abstract

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

Highlights

Interneurons are involved in fundamental aspects of brain function playing a key role in the operation of neuronal networks (Kullmann, 2011)
To investigate the consequences of interneuron-astrocyte signaling on excitatory synaptic transmission, we performed whole-cell recordings from pairs of GABAergic interneurons and CA1 pyramidal neurons, while monitoring both the excitatory postsynaptic transmission (EPSC) at putative single CA3-CA1 synapses (Dobrunz and Stevens, 1997; Navarrete and Araque, 2010; Perea and Araque, 2007) and Ca2+ signals in astrocytes (Figure 1A and Figure 1—figure supplement 1A–C)
Because interneuron activity has been shown to elevate astrocyte Ca2+ via activation of astrocytic GABAB receptors (Kang et al, 1998; Mariotti et al, 2016; Serrano et al, 2006), and Ca2+-dependent release of gliotransmitters from astrocytes modulate synaptic transmission (Di Castro et al, 2011; Henneberger et al, 2010; Jourdain et al, 2007; Navarrete et al, 2012; Panatier et al, 2011; Perea and Araque, 2007; Serrano et al, 2006), we investigated the participation of the astrocyte Ca2+ signal in the interneuron-induced synaptic potentiation

Summary

Introduction

Interneurons are involved in fundamental aspects of brain function playing a key role in the operation of neuronal networks (Kullmann, 2011). Astrocytes, considered for decades to play merely supportive roles for neurons, have emerged as active regulatory elements directly involved in synaptic physiology (Perea et al, 2009). Controversial (Agulhon et al, 2010; Hamilton and Attwell, 2010), astrocyte Ca2+ signal have been shown to stimulate the release of active substances, so-called gliotransmitters, that can regulate neuronal excitability and synaptic transmission and plasticity (Araque et al, 2014; Haydon and Carmignoto, 2006; Perea et al, 2009; Volterra and Meldolesi, 2005). The functional interaction between astrocytes and neurons suggests an active role of astrocytes in brain function (Araque et al, 2014; Pannasch and Rouach, 2013)

Methods

Results

Conclusion