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.

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus

“…The FD Rapid GolgiStain kit (FD Neuro Technologies, Baltimore, MD) was used as recently described (Castaneda et al, 2015). Secondary apical dendrites of pyramidal neurons from the CA1 region were selected for spine analyses (bregma -2.3 to -4.3) (Paxinos and Watson, 1982).…”

Electroacupuncture Regulates Hippocampal Synaptic Plasticity via miR-134-Mediated LIMK1 Function in Rats with Ischemic Stroke

“…Our previous study has shown that EA at Baihui (DU20) and Shenting (DU24) acupoints could improve cognitive impairment through Rho GTPases to enhance dendritic plasticity in rats with ischemic stroke [27]. Interestingly, it has been suggested that the activation of the Rho GTPases signaling is essential for LIMK1 activation by phosphorylation on threonine 508, which is widely known as master regulator of actin dynamics [28, 29]. Thus, the study aimed to elucidate whether EA at the DU20 and DU24 acupoints could improve the cognitive deficits in rats with ischemic stroke via miRNA-LIMK1-mediated synaptic plasticity to enhance spatial reference learning and memory.…”

Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice

“…For example, social defeat induces both neuroendocrine and behavioral modifications (Keeney et al., 2001), as well as neurobiological alterations across several brain regions that are particularly vulnerable to stress, including the hippocampus (Tse et al., 2014). More specifically, it is reported that the CA1 subregion of the hippocampus displays morphological changes as a consequence of stress exposure (Castaneda et al., 2015, Sebastian et al., 2013a); however, this relationship has yet to be examined during the juvenile stage of development, as a function of social stress specifically. Thus, in order to characterize the effects of social stress on hippocampal spine morphology during adolescence, we examined the expression of synaptic markers within CA1 spines.…”