Editors' ChoiceNeuroscience

The new stars of synaptic regulation

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Science Translational Medicine  25 Oct 2017:
Vol. 9, Issue 413, eaap8174
DOI: 10.1126/scitranslmed.aap8174

Abstract

Astrocytes regulate synaptic function in amygdala.

Central and basolateral nuclei are the two main structures forming the amygdala, a brain area critically implicated in multiple behaviors ranging from feeding to fear and anxiety. The central amygdala constitutes the major output structure, and multiple studies have elucidated the role that various afferents to this region play in regulating local neuronal activity. However, the role of extra neuronal components in modulating central amygdala activity remains largely unknown. In this study, Martin-Fernandez et al. use pharmacology, genetic, and chemogenetic approaches; in vitro electrophysiological recordings; and in vivo behavioral analysis to explore the role of the astrocyte population in regulating synaptic activity in the central amygdala. The authors showed that directly depolarizing neurons in the medial subdivision of central amygdala (CeM), which has previously been shown to result in endocannabinoid (eCB) release, was sufficient to increase CeM inhibitory postsynaptic currents (IPSCs) from the lateral subdivision of the central amygdala (CeL) and decrease excitatory postsynaptic currents (EPSCs) from basolateral amygdala (BLA). By disrupting cannabinoid receptor 1 (CB1R) signaling either pharmacologically or selectively in astrocytes using transgenic tools, they showed that eCB dependent activation of astrocytic CBR1 was necessary for promoting these physiological responses. CBR1 signaling regulated calcium entry into astrocytes, and sequestering astrocytic calcium suppressed the synaptic responses induced by CeM neuron depolarization. Furthermore, exogenously increasing calcium in astrocytes using designer receptors exclusively activated by designer drugs (DREADDs) was sufficient to recapitulate the effects of CeM neuron depolarization. Thus, CeM astrocytic calcium entry was necessary and sufficient to increase IPSCs from CeL afferents and decrease EPSCs from BLA afferents.

The results implicated a presynaptic mechanism; therefore, the authors also tested whether gliotransmitter release was involved in the effects induced by astrocytic calcium entry. Adenosine A2A and Adenosine A1 receptor antagonists blocked CeL-evoked IPSCs and BLA-evoked EPSCs, respectively. This finding demonstrated that ATP/adenosine was the gliotransmitter critical for the physiological observations. Last, the study shows that directly modulating CeM astrocyte activity using DREADDS in vivo was sufficient to promote acute extinction of fear.

Future studies to determine the impact of astrocyte activation on other amygdala dependent behaviors including feeding and reward are warranted. Nevertheless, by discovering the mechanism whereby astrocytes regulate CeM activity, the authors highlight a potential cellular target for developing therapeutics to treat psychiatric disorders such as post-traumatic stress.

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