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Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):650-655. doi: 10.1073/pnas.1910322116. Epub 2019 Dec 16.

Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.

Author information

1
Department of Neurobiology, National Centre for Biological Sciences, 560065 Bangalore, India.
2
Centre for Discovery Brain Sciences, University of Edinburgh, EH8 9XD Edinburgh, United Kingdom.
3
Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
4
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
5
Department of Molecular Physiology, Leiden Institute of Chemistry, 2300 RA Leiden, The Netherlands.
6
Deaprtment of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 1N4, Canada.
7
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226.
8
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226.
9
Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB T2N 1N4, Canada.
10
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@mail.rockefeller.edu mnhill@ucalgary.ca shona@ncbs.res.in.
11
Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada; mcewen@mail.rockefeller.edu mnhill@ucalgary.ca shona@ncbs.res.in.
12
Department of Neurobiology, National Centre for Biological Sciences, 560065 Bangalore, India; mcewen@mail.rockefeller.edu mnhill@ucalgary.ca shona@ncbs.res.in.
13
Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, 560065 Bangalore, India.

Abstract

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CB1R), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced N-arachidonoylethanolamine (AEA), an endogenous ligand of CB1R. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.

KEYWORDS:

BLA; FAAH; eCB; stress

PMID:
31843894
PMCID:
PMC6955336
[Available on 2020-06-16]
DOI:
10.1073/pnas.1910322116

Conflict of interest statement

Competing interest statement: The authors declare a competing interest. This research was supported, in part, by an unrestricted operating grant to B.S.M. from Johnson & Johnson Pharmaceuticals. The funding body had no role in the design of this study, collection or analysis of the data, or decision to publish, outside of the development of the pharmacological compound, JNJ-40355003, which was used in this study.

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