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Cell. 2016 Jul 28;166(3):716-728. doi: 10.1016/j.cell.2016.06.026. Epub 2016 Jul 14.

Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

Author information

1
School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
2
National Institute of Biological Sciences, Beijing 102206, China; PTN Graduate Program, Peking University School of Life Sciences, Beijing 100081, China.
3
National Institute of Biological Sciences, Beijing 102206, China.
4
Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
5
School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China. Electronic address: luominmin@nibs.ac.cn.

Abstract

Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.

PMID:
27426949
DOI:
10.1016/j.cell.2016.06.026
[Indexed for MEDLINE]
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