Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model

Abstract

Background. Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods. To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results. Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions. These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine’s lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review

“…Ketamine can be sublingual, oral, intramuscular, saline, transmucosal, intranasal, and intravenous. Abdoulaye et al [ 111 ] established that the administration of ketamine aids in faster and more positive impacts on depressive symptoms. The injection of ketamine in individuals suffering from PSD could increase the concentration of atrial natriuretic peptide synthesized in atrial myocytes, thereby exerting anti-depression effects [ 112 ].…”

The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity

“…Ketamine’s modulatory actions also converge on to pathways downstream of NMDAR. In a poststroke depression model of rats, ketamine administration significantly improved antidepressant-like symptoms ( 155 ). Along with this, there was an upregulation of subtype NMDAR2-β and downregulation of subtype NMDAR2-α, as well as their downstream signaling proteins, β-CaMKII and α-phosphorylation, respectively, in the dentate gyrus ( 155 ).…”

“…In a poststroke depression model of rats, ketamine administration significantly improved antidepressant-like symptoms ( 155 ). Along with this, there was an upregulation of subtype NMDAR2-β and downregulation of subtype NMDAR2-α, as well as their downstream signaling proteins, β-CaMKII and α-phosphorylation, respectively, in the dentate gyrus ( 155 ). Interestingly, no effects on NR1 and NR3 subtypes were seen, suggesting that ketamine is not dependent on all subunits of NMDARs ( 155 ).…”

Prophylactic Zinc Administration Combined with Swimming Exercise Prevents Cognitive-Emotional Disturbances and Tissue Injury following a Transient Hypoxic-Ischemic Insult in the Rat

“…In addition, several studies show that the administration of NMDA receptor antagonists prevented tissue damage [ 107 , 108 ] and modified some aspects of behavior [ 108 ], which can be enhanced by hypothermia caused by anesthesia [ 109 ]. In this work, we used ketamine which has been useful in models of ischemia, being capable of reducing the damage when administered superacute and therapeutically mode [ 110 , 111 ], due to its inhibitor effect on glutamate receptors [ 112 ].…”