期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 93, 期 10, 页码 1476-1491出版社
WILEY
DOI: 10.1002/jnr.23602
关键词
behavior; Rho proteins; stress; depression; N-cadherin; beta-catenin; RRID; RGD_70508; RRID; AB_228341; RRID; AB_228307; RRID; SCR_013725; RRID: rid_000081; RRID; AB_476743; RRID; AB_398236; RRID; AB_634603; RRID; AB_2491619; RRID; AB_260391; RRID; AB_330238; RRID; AB_10708808; RRID: AB_1031185; RRID; AB_1642257; resource ID; SCR_013726
资金
- FONDECYT [1120528, 1080489]
- FONDEQUIP [EQM120114, FID-1998-2001]
- MECESUP [2005-2009]
Chronic stress promotes cognitive impairment and dendritic spine loss in hippocampal neurons. In this animal model of depression, spine loss probably involves a weakening of the interaction between pre- and postsynaptic cell adhesion molecules, such as N-cadherin, followed by disruption of the cytoskeleton. N-cadherin, in concert with catenin, stabilizes the cytoskeleton through Rho-family GTPases. Via their effector LIM kinase (LIMK), RhoA and ras-related C3 botulinum toxin substrate 1 (RAC) GTPases phosphorylate and inhibit cofilin, an actin-depolymerizing molecule, favoring spine growth. Additionally, RhoA, through Rho kinase (ROCK), inactivates myosin phosphatase through phosphorylation of the myosin-binding subunit (MYPT1), producing actomyosin contraction and probable spine loss. Some micro-RNAs negatively control the translation of specific mRNAs involved in Rho GTPase signaling. For example, miR-138 indirectly activates RhoA, and miR-134 reduces LIMK1 levels, resulting in spine shrinkage; in contrast, miR-132 activates RAC1, promoting spine formation. We evaluated whether N-cadherin/-catenin and Rho signaling is sensitive to chronic restraint stress. Stressed rats exhibit anhedonia, impaired associative learning, and immobility in the forced swim test and reduction in N-cadherin levels but not -catenin in the hippocampus. We observed a reduction in spine number in the apical dendrites of CA1 pyramidal neurons, with no effect on the levels of miR-132 or miR-134. Although the stress did not modify the RAC-LIMK-cofilin signaling pathway, we observed increased phospho-MYPT1 levels, probably mediated by RhoA-ROCK activation. Furthermore, chronic stress raises the levels of miR-138 in accordance with the observed activation of the RhoA-ROCK pathway. Our findings suggest that a dysregulation of RhoA-ROCK activity by chronic stress could potentially underlie spine loss in hippocampal neurons. (c) 2015 Wiley Periodicals, Inc.
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