Ketamine destabilizes growth of dendritic spines in developing hippocampal neurons in�vitro via a Rho‑dependent mechanism

Abstract

The safety of anesthetics on the developing brain has caused concern. Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely used as a general pediatric anesthetic. Recent studies suggested that ketamine alters the plasticity of dendritic spines in the developing brain and may be an important contributing factor to learning and cognitive impairment. However, the underlying molecular mechanism remains poorly understood. Therefore, the aim of the present study was to investigate the effect of ketamine on the plasticity of dendritic spines in cultured hippocampal neurons and the potential underlying mechanisms. After 5 days in vitro, rat hippocampal neurons were exposed to different concentrations (100, 300 and 500 µM) of ketamine for 6 h. Ketamine decreased the number and length of dendritic spines in a dose-dependent manner. Ketamine at a concentration of 300 µM caused an upregulation of transforming protein RhoA (RhoA) and Rho-associated kinase (ROCK) protein. These effects were inhibited by the ROCK inhibitor Y27632. These results suggested that ketamine induces loss and shortening of dendritic spines in hippocampal neurons via activation of the RhoA/ROCK signaling pathway.

Antipsychotic Drugs Reverse MK801-Inhibited Cell Migration and F-actin Condensation by Modulating the Rho Signaling Pathway in B35 Cells

“…Neuronal plasticity in the brain has also been reported to be closely related to psychotic disorders, including schizophrenia. In various recent studies, APDs were also shown to regulate neuronal plasticity [14][15][16], which has been found to be regulated by the Rho signaling pathway [17][18][19][20]. These findings suggest that APDs might modulate neuronal cell plasticity by regulating Rho signaling pathway.…”

Quantification of Dendritic Spines Remodeling under Physiological Stimuli and in Pathological Conditions

“…For in vivo live cell imaging, transgenic mice expressing fluorescent proteins (GFP/RFP/YFP) within whole brain, brain regions, or specific cell types are used [ 38 , 40 , 41 , 45 , 103 ]. It is worth emphasizing that several anesthetic drugs affect spine dynamics [ 104 , 105 ], which can constitute a crucial element during in vivo live cell imaging under anesthesia.…”

Dendritic spine remodeling and plasticity under general anesthesia

“…Both, acute and lasting effects of single or repeated ketamine exposure on dendritic spines has been shown by numerous reports. Dendritic spines of developing neurons emerge to be especially sensitive to ketamine, with a single time exposure of 5 DIV rat neuronal cultures causing a decrease in both, spine number and length (Jiang et al 2018 ). Under these settings, inhibition of RhoA/ROCK signaling by Y27632 was reported to attenuate the effects of ketamine on spines, suggesting that ketamine-induced changes in dendritic spine morphology and synaptic plasticity involve Rho/ROCK mechanisms (Jiang et al 2018 ).…”

“…Likewise, in children under 3 years of age, general anesthesia has been reported to increase the risk of learning and memory deficit throughout puberty and into adulthood (Flick et al 2011 ; Sun 2010 ; Wilder et al 2009 ). An increasing number of reports have also shown detrimental effects of widely used general anesthetics in neuronal cultures, with outcomes varying, depending on the developmental stage of neurons (Head et al 2009 ; Jiang et al 2018 ). These findings are in agreement with numerous studies in rodents and primates, suggesting that the use of dissociative anesthetics during critical periods of development may induce lasting deficits of specific brain mechanisms and functions (Paule et al 2011 ; Scallet et al 2004 ).…”

“…Importantly, these small protrusions of dendrites reveal a wide range of morphologies, with their changes related to a variety of specific neuronal processes and functions (Leuner and Shors 2004 ; Yuste 2010 ). Although the prevalent view is that developing neurons are especially sensitive to the lasting impact of general anesthetics, growing data shows that destabilizing effects of general anesthetics on spines and synaptic connections can occur in the mature brain as well, i.e., might be partially independent of the developmental processes in neurons (Crosby et al 2010 ; Jiang et al 2018 ; Platholi et al 2014 ).…”