Ketamine Rescues Hippocampal Reelin Expression and Synaptic Markers in the Repeated-Corticosterone Chronic Stress Paradigm

Abstract

Depression is the leading cause of disability worldwide, which necessitates novel therapeutics and biomarkers to approach treatment of this neuropsychiatric disorder. To assess potential mechanisms underlying the fast-acting antidepressant actions of ketamine we used a repeated corticosterone paradigm in adult male rats to assess the effects of ketamine on reelin-positive cells, a protein largely implicated in the pathophysiology of depression. We also assessed the effects of reelin and ketamine on hippocampal and cerebellar synpatosomes, and on serotonin transporter clustering in peripheral lymphocytes to determine reelin and ketamine’s impact at the synaptic and peripheral levels. Reelin and ketamine similarly rescue synaptic expression of mTOR and p-mTOR that were decreased by corticosterone. Reelin, but not ketamine, was able to rescue patterns of serotonin transporter clustering in the periphery. These findings display ketamine as a powerful modulator of reelin expression and lend strength to further evaluation of the putative fast antidepressant-like actions of reelin.

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

“…Ketamine administration rapidly activates the mTOR pathway in animal models, and consequently increases levels of associated signaling proteins dose-dependently, such as phospho- eukaryotic initiation factor 4E binding protein 1 (p4E-BP), p70S6 kinase (p70S6K), extracellular signal-regulated kinase (ERK), and Akt (also named protein kinase B, PKB), an effect that is sustained for at least 72 h ( 73 ). Levels of phosphorylated mTOR increase in rat hippocampus and dorsal raphe nucleus post ketamine exposure ( 61 , 74 ). Blocking the mTOR pathway with rapamycin results in inhibition of ketamine’s behavioral and molecular effects ( 73 , 75 ) including increases in synaptic proteins such as postsynaptic density protein 95 (PSD-95), and GluA1 in the PFC ( 73 , 75 ) and hippocampus ( 76 ).…”

Ketamine as a pharmacological tool for the preclinical study of memory deficit in schizophrenia

“…The acute injection of KET can increase synaptic and structural plasticity in brain structures such as the Hp and PFC (Aleksandrova et al, 2010;Grieco et al, 2020; Kang et al, 2020), an effect apparently mediated by the mTORC1 signaling pathway (Pazini et al, 2020). Some studies show that acute injection of KET induces a transient increase in phospho-mTOR and its targets, phospho-p70S6 kinase and phospho-4E-BP1, in PFC and Hp in rodents (Zhang et al, 2017;Johnston et al al., 2020;Pazini et al, 2020). The inhibition of mTORC1 can slow down the behavioral and molecular events that attribute to KET and its antidepressant effect (Abdallah et al, 2020).…”

“…The acute injection of KET can increase synaptic and structural plasticity in brain regions such as Hp and prefrontal cortex (PFC) (Aleksandrova et al ., 2010; Grieco et al , 2020; Kang et al , 2020), an effect apparently mediated by the mTORC1 signaling pathway (Pazini et al , 2020). Accordingly, acute injection of KET induces a transient increase in phospho-mTOR and its targets, phospho-p70S6 kinase and phospho-4E-BP1, in both PFC and Hp of rodents (Zhang et al ., 2017; Johnston et al , 2020; Pazini et al , 2020), whereas mTORC1 inhibition can slow down the behavioral and molecular events that may give to KET its antidepressant effect (Abdallah et al , 2020). In this line, mTORC1 pathway seems to modulate other metabolic processes such as nucleotide and lipid synthesis, glucose metabolism, autophagy, lysosome biogenesis, and proteasome assembly (Yanh et al ., 2020) (See Fig.…”

How Stress Influences the Dynamic Plasticity of the Brain’s Extracellular Matrix

“…These findings suggest that developmental and acute adult stress may produce adaptive stress responses through augmented reelin signaling, while chronic adult stress may lead to dysfunction via a reduction in reelin expression. Along these lines, it may be relevant that antidepressant drug treatment reverses stress-induced decreases in reelin expression (Fenton et al, 2015;Johnston et al, 2020), and that hippocampal reelin infusions can reverse stress-induced behavioral dysfunction (Brymer et al, 2020). Laminin expression is also decreased after chronic stress in both the adult hippocampus and frontal cortex (Laifenfeld et al, 2005a;Rodríguez-Arias et al, 2017).…”