S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 GTPase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats

Abstract

Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50µg, ICV) treatment. The depressionlike behavior of rats was evaluated by sucrose preference test and open-eld test. The protein expression of Rac1, Glur1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as Glur1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The speci c mechanism of Sketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.

TIAM1-mediated synaptic plasticity underlies comorbid depression–like and ketamine antidepressant–like actions in chronic pain

“…Whereas neuronal atrophy and synaptic loss in the PFC and hippocampus are hypothesized to cause stress-induced depression ( 56 ), our data and others suggest that spinogenesis and synaptic potentiation in the ACC promote chronic pain–induced depressive-like behavior ( 8 , 9 ). Rac1 signaling has also been implicated in stress-induced depression ( 57 , 58 ) and the antidepressant-like effects of ketamine ( 58 ). However, contrary to our findings that ketamine treatment reduces chronic pain–induced depressive-like behaviors by blocking increases in Tiam1-Rac1 activation, dendritic spine density, and synaptic NMDAR levels and function in the ACC, ketamine was shown to improve depression-like behaviors in stressed rats by upregulating Rac1 activity and increasing dendritic spine density and synaptic-related protein expression in the hippocampus ( 58 ).…”

“…Rac1 signaling has also been implicated in stress-induced depression ( 57 , 58 ) and the antidepressant-like effects of ketamine ( 58 ). However, contrary to our findings that ketamine treatment reduces chronic pain–induced depressive-like behaviors by blocking increases in Tiam1-Rac1 activation, dendritic spine density, and synaptic NMDAR levels and function in the ACC, ketamine was shown to improve depression-like behaviors in stressed rats by upregulating Rac1 activity and increasing dendritic spine density and synaptic-related protein expression in the hippocampus ( 58 ). In both cases, stress and chronic pain appear to drive alterations in Tiam1-Rac1 signaling and synapse connectivity and function that are rescued by ketamine treatment, but the manner of change and the brain regions/neural circuits involved may differ.…”

The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC

“…Furthermore, a single dose of rapastinel (GLYX-13), which, like mixRL, is a potential RAAD, reverses these effects and restores LTP efficiency to the control level 24 h after treatment [ 32 ]. LTP impairments under CUMS in rats have also been shown in the hippocampus, and ( S )-ketamine, administered for seven days, alleviates these effects in a Rac1 GTPase-dependent manner [ 33 ]. Similarly, when using the Wistar Kyoto (WKY) rat model of depression, LTP impairment was observed in the hippocampus, and a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescues these LTP deficits at 3.5 h following injection, with residual effects at 24 h [ 34 ].…”

Postsynaptic Proteins at Excitatory Synapses in the Brain—Relationship with Depressive Disorders

“…Chronic ketamine administration caused a decrease in AMPARs, both gene and protein levels in the whole hippocampus and CA1 region [ 130 ]. Moreover, treatment with infenprodil, fluoxetine, and S-ketamine, venlafaxine, and NaHS normalized GluA1 protein stress-induced changes in the medial prefrontal cortex and hippocampus, respectively [ 145 , 150 , 154 , 156 , 162 ]. In its turn, the application of ketamine and memantine, induced a significant increase in the pS845-GluA1 protein subunit in the hippocampus [ 160 ].…”

“…Interestingly, PSD-95 protein levels were significantly higher in the basolateral amygdala after stress [ 136 ]. Application of fluoxetine, asioaticoside in mice, and ketamine or sodium hydrosulfide—NaHS (CA1, CA3 region) in rats increased PSD-95 protein levels in the hippocampus [ 156 , 162 , 166 ]. In contrast, in the basolateral amygdala, fluoxetine increased protein levels [ 136 ].…”