Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents.
BACKGROUND
Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown.


RESULTS
We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.


CONCLUSIONS
Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.
Zhi-Peng
ZP
Liu
Chen
C
Song
Min
M
Wang
Ye
Y
He
Xiao-Bin
XB
Xu
Han-Qing
HQ
Pan
Wen-Bing
WB
Chen
Wei-Jie
WJ
Peng
Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, China. panbingxing@ncu.edu.cn.
Bing-Xing
BX
Pan
D000200:Action Potentials / Q000187:drug effects; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002908:Chronic Disease; D003345:Corticosterone / Q000096:biosynthesis; D007103:Immobilization; D007266:Inhibition, Psychological; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011963:Receptors, GABA-A / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D011965:Receptors, Glucocorticoid; D005680:gamma-Aminobutyric Acid; D003345:Corticosterone