Castañeda Patricia, Muñoz Mauricio, García-Rojo Gonzalo, Ulloa José L, Bravo Javier A, Márquez Ruth, García-Pérez M Alexandra, Arancibia Damaris, Araneda Karina, Rojas Paulina S, Mondaca-Ruff David, Díaz-Véliz Gabriela, Mora Sergio, Aliaga Esteban, Fiedler Jenny L
Department of Biology, Faculty of Sciences, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile.
Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
J Neurosci Res. 2015 Oct;93(10):1476-91. doi: 10.1002/jnr.23602. Epub 2015 May 23.
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/β-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 β-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.
慢性应激会促进海马神经元的认知障碍和树突棘丢失。在这种抑郁症动物模型中，树突棘丢失可能涉及突触前和突触后细胞黏附分子（如N-钙黏蛋白）之间相互作用的减弱，随后是细胞骨架的破坏。N-钙黏蛋白与连环蛋白协同作用，通过Rho家族小G蛋白稳定细胞骨架。RhoA和Ras相关的C3肉毒杆菌毒素底物1（RAC）小G蛋白通过其效应分子LIM激酶（LIMK）使肌动蛋白解聚分子丝切蛋白磷酸化并抑制丝切蛋白，从而促进树突棘生长。此外，RhoA通过Rho激酶（ROCK）使肌球蛋白磷酸酶的肌球蛋白结合亚基（MYPT1）磷酸化而使其失活，产生肌动球蛋白收缩并可能导致树突棘丢失。一些微小RNA负向调控参与Rho小G蛋白信号传导的特定mRNA的翻译。例如，miR-138间接激活RhoA，miR-134降低LIMK1水平，导致树突棘萎缩；相反，miR-132激活RAC1，促进树突棘形成。我们评估了N-钙黏蛋白/β-连环蛋白和Rho信号传导是否对慢性束缚应激敏感。应激大鼠表现出快感缺失、联想学习受损、在强迫游泳试验中不动，并且海马中N-钙黏蛋白水平降低，但β-连环蛋白水平未降低。我们观察到CA1锥体神经元顶端树突中的树突棘数量减少，而对miR-132或miR-134的水平没有影响。虽然应激未改变RAC-LIMK-丝切蛋白信号通路，但我们观察到磷酸化MYPT1水平升高，这可能是由RhoA-ROCK激活介导的。此外，根据观察到的RhoA-ROCK通路激活情况，慢性应激会提高miR-138的水平。我们的研究结果表明，慢性应激导致的RhoA-ROCK活性失调可能是海马神经元树突棘丢失的潜在原因。
