Recent in vitro evidence indicates that astrocytes can modulate synaptic plasticity by releasing neuroactive substances (gliotransmitters). However, whether gliotransmitter release from astrocytes is necessary for higher brain function in vivo , particularly for memory, as well as the contribution of connexin (Cx) hemichannels to gliotransmitter release, remain elusive. Here, we microinfused into the rat basolateral amygdala (BLA) TAT‐Cx43L2, a peptide that selectively inhibits Cx43‐hemichannel opening while maintaining synaptic transmission or interastrocyte gap junctional communication. In vivo blockade of Cx43 hemichannels during memory consolidation induced amnesia for auditory fear conditioning, as assessed 24 h after training, without affecting short‐term memory, locomotion, or shock reactivity. The amnesic effect was transitory, specific for memory consolidation, and was confirmed after microinfusion of Gap27, another Cx43‐hemichannel blocker. Learning capacity was recovered after coinfusion of TAT‐Cx43L2 and a mixture of putative gliotransmitters (glutamate, glutamine, lactate, d ‐serine, glycine, and ATP). We propose that gliotransmitter release from astrocytes through Cx43 hemichannels is necessary for fear memory consolidation at the BLA. Thus, the present study is the first to demonstrate a physiological role for astroglial Cx43 hemichannels in brain function, making these channels a novel pharmacological target for the treatment of psychiatric disorders, including post‐traumatic stress disorder.—Stehberg, J., Moraga‐Amaro, R., Salazar, C., Becerra, A., Echeverría, C., Orellana, J. A., Bultynck, G., Ponsaerts, R., Leybaert, L., Simon, F., Sáez, J. C., Retamal, M. A. Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala. FASEB J. 26, 3649–3657 (2012). www.fasebj.org

The role of astrocytes in brain function has evolved over the last decade, from support cells to active participants in the neuronal synapse through the release of “gliotransmitters”. Astrocytes express receptors for most neurotransmitters and respond to them through Ca2+ intracellular oscillations and propagation of intercellular Ca2+ waves. While such waves are able to propagate among neighboring astrocytes through gap junctions, thereby activating several astrocytes simultaneously, they can also trigger the release of gliotransmitters, including glutamate, d-serine, glycine, ATP, adenosine or GABA. There are several mechanisms by which gliotransmitter release occurs, including functional hemichannels. These gliotransmitters can activate neighboring astrocytes and participate in the propagation of intercellular Ca2+ waves, or activate pre- and post-synaptic receptors, including NMDA, AMPA and purinergic receptors. In consequence, hemichannels could play a pivotal role in astrocyte-to-astrocyte communication and astrocyte-to-neuron cross-talk. Recent evidence suggests that astroglial hemichannels are involved in higher brain functions including memory and glucose sensing. The present review will focus on the role of hemichannels in astrocyte-to-astrocyte and astrocyte-to neuron communication and in brain physiology.

The human insula has been consistently reported to be overactivated in all anxiety disorders, activation which has been suggested to be proportional to the level of anxiety and shown to decrease with effective anxiolytic treatment. Nonetheless, studies evaluating the direct role of the insula in anxiety are lacking. Here, we set out to investigate the role of the rodent insula in anxiety by either inactivating different insular regions via microinjections of glutamatergic AMPA receptor antagonist CNQX or activating them by microinjection of GABA receptor antagonist bicuculline in rats, before measuring anxiety-like behavior using the elevated plus maze. Inactivation of caudal and medial insular regions induced anxiogenic effects, while their activation induced anxiolytic effects. In contrast, inactivation of more rostral areas induced anxiolytic effects and their activation, anxiogenic effects. These results suggest that the insula in the rat has a role in the modulation of anxiety-like behavior in rats, showing regional differences; rostral regions have an anxiogenic role, while medial and caudal regions have an anxiolytic role, with a transition area around bregma +0.5. The present study suggests that the insula has a direct role in anxiety.

Under physiological conditions, astroglial hemichannels and pannexin channels allow the release of gliotransmitters from astrocytes. These gliotransmitters are critical in modulating synaptic transmission, plasticity and memory. However, recent evidence suggests that under pathological conditions, they may be central in the development of various neurodegenerative diseases. Here we review current literature on the role of astroglial hemichannels and pannexin channels in memory, stress and the development of neurodegenerative diseases, and propose that astroglial connexin hemichannels and pannexin channels are not only crucial for normal brain function, including memory, but also a potential target for the treatment of neurodegenerative diseases.