title: Association of N-cadherin levels and downstream effectors of Rho GTPases with dendritic spine loss induced by chronic stress in rat hippocampal neurons.
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.
authors.affiliation: Department of Biology, Faculty of Sciences, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Castañeda
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: García-Rojo
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: José L
authors.initials: JL
authors.lastname: Ulloa
authors.affiliation: Grupo de NeuroGastroBioquímica, Laboratorio de Química Biológica, Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Bravo
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Ruth
authors.initials: R
authors.lastname: Márquez
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: M Alexandra
authors.initials: MA
authors.lastname: García-Pérez
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Damaris
authors.initials: D
authors.lastname: Arancibia
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Karina
authors.initials: K
authors.lastname: Araneda
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Paulina S
authors.initials: PS
authors.lastname: Rojas
authors.affiliation: Graduate Student PhD Program, Department of Pharmacology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Mondaca-Ruff
authors.affiliation: Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Díaz-Véliz
authors.affiliation: Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora
authors.affiliation: Escuela de Kinesiología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
authors.forename: Esteban
authors.initials: E
authors.lastname: Aliaga
authors.affiliation: Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Fiedler
mesh_terms: D000818:Animals; D001362:Avoidance Learning; D001835:Body Weight / Q000502:physiology; D015820:Cadherins / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D003863:Depression / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013312:Stress, Physiological; D013395:Sucrose / Q000378:metabolism; D013549:Sweetening Agents / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D015820:Cadherins; D035683:MicroRNAs; D013549:Sweetening Agents; D051176:beta Catenin; D013395:Sucrose; D054460:rho-Associated Kinases
keywords: AB_10708808; AB_1642257; AB_228307; AB_228341; AB_2491619; AB_260391; AB_330238; AB_398236; AB_476743; AB_634603; N-cadherin; RGD_70508; RRID; RRID: AB_1031185; RRID: rid_000081; Rho proteins; SCR_013725; SCR_013726; behavior; depression; resource ID; stress; β-catenin