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Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons Through NKCC1 Upregulation

Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons Through NKCC1 Upregulation

Yonggang Gao, Jing-Jing Zhou, Yun Zhu, Therese Kosten, De-Pei Li

Neuroendocrinology. 2017;104(2):194-208.

PMID: 27077366

Abstract:

Introduction:
Prolonged and repeated stresses cause hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The corticotrophin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) are an essential component of the HPA axis.
Materials and methods:
Chronic unpredictable mild stress (CUMS) was induced in Sprague-Dawley rats. GABA reversal potentials (EGABA) were determined by using gramicidin-perforated recordings in identified PVN-CRH neurons through expressing enhanced green fluorescent protein driven by the CRH promoter. Plasma corticosterone (CORT) levels were measured in rats implanted with a cannula targeting the lateral ventricles and PVN.
Results:
Blocking the GABAA receptor in the PVN with gabazine significantly increased plasma CORT levels in unstressed rats but did not change CORT levels in CUMS rats. CUMS caused a depolarizing shift in EGABA in PVN-CRH neurons compared with EGABA in PVN-CRH neurons in unstressed rats. Furthermore, CUMS induced a long-lasting increase in expression levels of the cation chloride cotransporter Na+-K+-Cl--Cl- (NKCC1) in the PVN but a transient decrease in expression levels of K+-Cl--Cl- in the PVN, which returned to the basal level 5 days after CUMS treatment. The NKCC1 inhibitor bumetanide decreased the basal firing activity of PVN-CRH neurons and normalized EGABA and the gabazine-induced excitatory effect on PVN-CRH neurons in CUMS rats. In addition, central administration of bumetanide decreased basal circulating CORT levels in CUMS rats.
Conclusions:
These data suggest that chronic stress impairs GABAergic inhibition, resulting in HPA axis hyperactivity through upregulation of NKCC1.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP28328532	Bumetanide Related Compound B		28328-53-2	Price

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