Association of N‐cadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons |
| |
| Authors: | José L. Ulloa Javier A. Bravo Ruth Márquez M. Alexandra García‐Pérez Damaris Arancibia Karina Araneda Paulina S. Rojas David Mondaca‐Ruff Gabriela Díaz‐Véliz Sergio Mora Esteban Aliaga Jenny L. Fiedler |
| |
| Affiliation: | 1. Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile;2. Grupo de NeuroGastroBioquímica, Laboratorio de Química Biológica, Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile;3. Graduate Student PhD Program, Department of Pharmacology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile;4. Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile;5. Escuela de Kinesiología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile |
| |
| Abstract: | 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. © 2015 Wiley Periodicals, Inc. |
| |
| Keywords: | behavior Rho proteins stress depression N‐cadherin β ‐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 |
|
|
