Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice

Asim, Mohammad; Hao, Bo; Waris, Abdul; Liang, Yimeng; Wang, Xiaoguang

doi:10.1016/j.mcn.2022.103723

Cited by 17 publications

(8 citation statements)

References 31 publications

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“…We found significantly higher pGluA1-S831 (CTRL, 1.000 and ketamine, 1.967 ± 0.488, p = 0.0149) and pGluA1-S845 levels (CTRL, 1.000 and ketamine, 2.399 ± 1.024, p = 0.0051) in ketamine-treated neurons than in the control (CTRL) ( Figure 1b ). This shows that ketamine treatment in cultured hippocampal neurons selectively increases GluA1 surface expression by increasing pGluA1-S831 and pGluA1-S845, which is consistent with the previous findings showing crucial role of GluA1 phosphorylation in rapid antidepressant responses of ketamine (Asim et al, 2022; Zhang et al, 2016; Zhang et al, 2017).…”

Section: Resultssupporting

confidence: 93%

“…Our new data suggest that ketamine-induced NMDAR antagonism significantly decreases neuronal Ca 2+ activity and subsequently calcineurin activity, leading to an increase in GluA1- containing, GluA2-lacking CP-AMPAR expression in the hippocampus via the elevation of GluA1 phosphorylation within one hour after ketamine treatment. Previous studies also demonstrate data consistent with our findings that GluA1 phosphorylation is crucial for ketamine-induced antidepressant effects in animals (Asim et al, 2022; Zhang et al, 2016; Zhang et al, 2017). These changes in glutamatergic synapses enhances synaptic plasticity in the hippocampus, which contributes to antidepressant effects in animals ( Figure 7b ).…”

Section: Discussionsupporting

confidence: 93%

“…1b). This shows that ketamine treatment in cultured hippocampal neurons selectively increases GluA1 surface expression by increasing pGluA1-S831 and pGluA1-S845, which is consistent with the previous findings showing crucial role of GluA1 phosphorylation in rapid antidepressant responses of ketamine (43)(44)(45).…”

Section: Ketamine Treatment Selectively Increases Glua1-containing Am...supporting

confidence: 93%

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Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Zaytseva

Bouckova

Wiles

et al. 2022

Preprint

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Ketamine is shown to enhance excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamines therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that inhibits excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+ - permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. When a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamines effects on animals behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Ketamine Treatment Selectively Increases Glua1-containing Am...supporting

confidence: 93%

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Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Zaytseva

Bouckova

Wiles

et al. 2022

Preprint

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“… 4 , 5 Stress leads to neural plasticity changes in the brain's valence‐coding systems that are strongly associated with depression. 6 , 7 , 8 , 9 The basolateral amygdala (BLA) is regarded as prominent among numerous valence‐coding brain regions. The BLA plays a crucial role in orienting and processing threats.…”

Section: Introductionmentioning

confidence: 99%

“…Stress is the foremost cause of synaptic dysfunction, which can be a potential therapeutic target for stress‐related mood disorders, including depression 4,5 . Stress leads to neural plasticity changes in the brain's valence‐coding systems that are strongly associated with depression 6–9 . The basolateral amygdala (BLA) is regarded as prominent among numerous valence‐coding brain regions.…”

Section: Introductionmentioning

confidence: 99%

Potentiated GABAergic neuronal activities in the basolateral amygdala alleviate stress‐induced depressive behaviors

Asim,

Wang,

Chen

et al. 2023

CNS Neurosci Ther

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AimsMajor depressive disorder is a severe psychiatric disorder that afflicts ~17% of the world population. Neuroimaging investigations of depressed patients have consistently reported the dysfunction of the basolateral amygdala in the pathophysiology of depression. However, how the BLA and related circuits are implicated in the pathogenesis of depression is poorly understood.MethodsHere, we combined fiber photometry, immediate early gene expression (c‐fos), optogenetics, chemogenetics, behavioral analysis, and viral tracing techniques to provide multiple lines of evidence of how the BLA neurons mediate depressive‐like behavior.ResultsWe demonstrated that the aversive stimuli elevated the neuronal activity of the excitatory BLA neurons (BLACAMKII neurons). Optogenetic activation of CAMKII neurons facilitates the induction of depressive‐like behavior while inhibition of these neurons alleviates the depressive‐like behavior. Next, we found that the chemogenetic inhibition of GABAergic neurons in the BLA (BLAGABA) increased the firing frequency of CAMKII neurons and mediates the depressive‐like phenotypes. Finally, through fiber photometry recording and chemogenetic manipulation, we proved that the activation of BLAGABA neurons inhibits BLACAMKII neuronal activity and alleviates depressive‐like behavior in the mice.ConclusionThus, through evaluating BLAGABA and BLACAMKII neurons by distinct interaction, the BLA regulates depressive‐like behavior.

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Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease

Asim,

Wang,

Waris

et al. 2024

BioFactors

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Cholecystokinin (CCK) plays a key role in various brain functions, including both health and disease states. Despite the extensive research conducted on CCK, there remain several important questions regarding its specific role in the brain. As a result, the existing body of literature on the subject is complex and sometimes conflicting. The primary objective of this review article is to provide a comprehensive overview of recent advancements in understanding the central nervous system role of CCK, with a specific emphasis on elucidating CCK's mechanisms for neuroplasticity, exploring its interactions with other neurotransmitters, and discussing its significant involvement in neurological disorders. Studies demonstrate that CCK mediates both inhibitory long‐term potentiation (iLTP) and excitatory long‐term potentiation (eLTP) in the brain. Activation of the GPR173 receptor could facilitate iLTP, while the Cholecystokinin B receptor (CCKBR) facilitates eLTP. CCK receptors' expression on different neurons regulates activity, neurotransmitter release, and plasticity, emphasizing CCK's role in modulating brain function. Furthermore, CCK plays a pivotal role in modulating emotional states, Alzheimer's disease, addiction, schizophrenia, and epileptic conditions. Targeting CCK cell types and circuits holds promise as a therapeutic strategy for alleviating these brain disorders.

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Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice

Cited by 17 publications

References 31 publications

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Potentiated GABAergic neuronal activities in the basolateral amygdala alleviate stress‐induced depressive behaviors

Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease

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Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice

Cited by 17 publications

References 31 publications

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus

Potentiated GABAergic neuronal activities in the basolateral amygdala alleviate stress‐induced depressive behaviors

Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease

Contact Info

Product

Resources

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Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus