Ketamine triggers rapid antidepressant effects by modulating synaptic plasticity in a new depressive-like mouse model based on astrocyte glutamate transporter GLT-1 knockdown in infralimbic cortex

Abstract Background A subanesthetic dose of ketamine provides rapid and effective antidepressant effects, but the molecular mechanism of this treatment remains elusive. Methods In this study, we investigated the role of CaMKIIα in the antidepressant effects of ketamine using an LPS-induced mouse model of depression, explored the different changes of CaMKIIα in the synaptic and extrasynaptic regions of the hippocampus, and clarified the relationship between CaMKIIα and GluN2B from extrasynaptic perspective. Results Ketamine (10 mg/kg, i.p.) administration attenuated the LPS-induced increase in extrasynaptic CaMKIIα activity (p-CaMKIIα) and extrasynaptic GluN2B localization and phosphorylation and that ketamine exerted antidepressant effects. Immunoprecipitation assay revealed that in the extrasynaptic region of the hippocampus, p-CaMKIIα bound to GluN2B, and ketamine administration attenuated the enhanced interaction between p-CaMKIIα and GluN2B induced by LPS. KN93, a CaMKIIα inhibitor, could also reverse the high level of extrasynaptic p-CaMKIIα, reduce hippocampal extrasynaptic GluN2B localization and phosphorylation, and exert antidepressant effects. Additional changes downstream of the ketamine-induced changes in extrasynaptic GluN2B included rescuing the downregulated expression of p-CREB, BDNF, and GluR1 and reversing the impaired induction of LTP in the hippocampus induced by LPS. Conclusion These results indicate that extrasynaptic CaMKIIα plays a key role in the cellular mechanism of ketamine's antidepressant effect and is related to the down-regulation of extrasynaptic GluN2B localization and phosphorylation and further affects synaptic plasticity.

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Faculty Opinions recommendation of Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725390463.793506606 ◽

2015 ◽

Author(s):

Mark J Millan

Keyword(s):

Down Syndrome ◽

Synaptic Plasticity ◽

Mouse Model

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The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Molecules ◽

10.3390/molecules26051372 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1372

Author(s):

Tengrui Shi ◽

Jianxi Song ◽

Guanying You ◽

Yujie Yang ◽

Qiong Liu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Synaptic Plasticity ◽

Mouse Model ◽

Mouse Models ◽

Knockout Mouse ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Knockout Mouse Model ◽

The Central Nervous System

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

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Lacto-N-fucopentaose-III ameliorates acute and persisting hippocampal synaptic plasticity and transmission deficits in a Gulf War Illness mouse model

Life Sciences ◽

10.1016/j.lfs.2021.119707 ◽

2021 ◽

pp. 119707

Author(s):

Kyle A. Brown ◽

Jessica M. Carpenter ◽

Collin J. Preston ◽

Helaina D. Ludwig ◽

Kendall B. Clay ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Gulf War ◽

Gulf War Illness ◽

Hippocampal Synaptic Plasticity

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Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20143407 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3407 ◽

Cited By ~ 2

Author(s):

Paola Imbriani ◽

Annalisa Tassone ◽

Maria Meringolo ◽

Giulia Ponterio ◽

Graziella Madeo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Synaptic Plasticity ◽

Mouse Model ◽

Caspase 3 ◽

Cysteine Proteases ◽

Synaptic Function ◽

Adult Brain ◽

Striatal Slices

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

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Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

PLoS ONE ◽

10.1371/journal.pone.0012845 ◽

2010 ◽

Vol 5 (9) ◽

pp. e12845 ◽

Cited By ~ 127

Author(s):

Tao Ma ◽

Charles A. Hoeffer ◽

Estibaliz Capetillo-Zarate ◽

Fangmin Yu ◽

Helen Wong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Mouse Model ◽

Mtor Pathway ◽

Model Of Alzheimer’S Disease

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The antidepressant effects of Ginsenoside Rg1 and Rb1 are involved in regulating NMDAR1 phosphorylation via mTOR-Akt-NF-kappa B pathway in CUMS mouse model

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po2-12-27 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO2-12-27

Author(s):

Yan Liu ◽

Yun-Long Zhang ◽

Jun-Rong Zhu ◽

Sui-Feng Liu ◽

Lei Wen

Keyword(s):

Mouse Model ◽

Ginsenoside Rg1 ◽

Nf Kappa B ◽

Antidepressant Effects

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Interaction between perineuronal nets and ketamine in antidepressant action

10.1101/2021.05.30.446326 ◽

2021 ◽

Author(s):

Calvin K Young ◽

Kachina G Kinley ◽

Neil McNaughton

Keyword(s):

Suicide Risk ◽

Forced Swim Test ◽

Perineuronal Nets ◽

Scaffolding Proteins ◽

Infralimbic Cortex ◽

Swim Test ◽

Forced Swim ◽

Antidepressant Effects ◽

Immobility Time ◽

Antidepressant Action

Depression is highly prevalent, increases suicide risk, and is now the leading cause of disability worldwide. Our ability to treat depression is hampered by the lack of understanding of its biological underpinnings and of the mode of action of effective treatments. We hypothesised that the scaffolding proteins in the medial frontal cortex play a major role in effective antidepressant action. We implanted cannulae into the infralimbic cortex to inject chABC and locally remove perineuronal nets and then tested for antidepressant effects with the forced swim test. We further tested if systemic injections of ketamine had an additive effect. Our preliminary data indicate that neither the removal of these scaffolding proteins nor ketamine were sufficient to decrease depression-like behaviour, but may interact synergistically to decrease immobility time in the forced swim test.

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