Ketamine May Exert Rapid Antidepressant Effects Through Modulation of Neuroplasticity, Autophagy, and Ferroptosis in the Habenular Nucleus

Zhang, Mengke; Lyu, Dongbin; Wang, Fan; Shi, Shuxiang; Wang, Meiti; Yang, Weichieh; Huang, Haijing; Wei, Zheyi; Chen, ShenTse; Xu, Yi; Wang, Hong

doi:10.1016/j.neuroscience.2022.10.015

Cited by 15 publications

(12 citation statements)

References 45 publications

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“…This is supported by work showing that a lower rheobase (minimum frequency required for an action potential) was recorded in excitatory neurons projecting from the m-PFC to the LHb in both a chronic stress paradigm and a genetic knockout (itpr2 knockout) model (54). LHb outputs, specifically to the dopaminergic VTA, have a similar increase in excitatory postsynaptic currents (52) and overall firing rate (77) (76,81). In line with the role of ßCaMKII to enhance glutamatergic synaptic transmission via AMPAR phosphorsphoylation and insertion into the synapse, the post-synaptic expression of calcium permeable AMPARs was increased following chronic stress exposure (36).…”

Section: Habenula Neuronal Firingmentioning

confidence: 81%

“…Stress-induced models consistently potentiate LHb glutamatergic transmission, shifting the excitatory/inhibitory (E:I) balance towards excitation (36, 50 69). Both stress-induced and genetic models of depression have reported significant elevations in ßCaMKII (which enhance glutamate activity) in the LHb (n=2) (76, 81). In line with the role of ßCaMKII to enhance glutamatergic synaptic transmission via AMPAR phosphorsphoylation and insertion into the synapse, the post-synaptic expression of calcium permeable AMPARs was increased following chronic stress exposure (36).…”

Section: Resultsmentioning

confidence: 99%

“…The small number of Indeed, in healthy rodents, direct stimulation of the LHb is sufficient to induce a depressive-like phenotype, suggesting LHb hyperactivity may be a primary pathology in depression (22,49). Preclinical evidence suggests molecular substrates involved in glutamatergic transmission in the Hb may be a valuable target to suppress neuronal firing (50,45,76,81). Overexpression of the enzyme, ßCaMKII, which promotes glutamatergic transmission, in the LHb induces symptoms of behavioural despair and anhedonia whereas blockade of ßCaMKII ameliorates these depressive-like behaviours (81).…”

Section: Discussionmentioning

confidence: 99%

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The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

Cameron,

Weston-Green,

Newell

2024

Preprint

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Background: The habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct stimulation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field. Methods: A systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across the databases Scopus, Web of Science and PubMed. Studies eligible for inclusion must have examined changes in the habenula in clinical cases of depression or preclinical models of depression. Results: Preclinical studies (n=57) measured markers of habenula activity (n=16) and neuronal firing (n=21), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n=13), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n=1), inflammatory (n=2), genomic (n=2) and circadian rhythm (n=2) abnormalities. Seven preclinical studies (12.2%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n=18) reported abnormalities in habenula connectivity (n=11), volume (n=5) and molecular markers (n=2). Clinical studies generally included male and female subjects (n=15), however, few of these studies examined sex as a biological variable (n=5) Conclusions: Both preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses.

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Section: Habenula Neuronal Firingmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

Cameron,

Weston-Green,

Newell

2024

Preprint

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“…Conversely, subanesthetic ketamine suppressed chronic restraint stress (CRS) induced ferroptosis by increasing FTH1 and GPX4 levels and decreasingTfr1 levels. 104 Recently, propofol presented a neuroprotective effect on neuronal ferroptosis. In HT-22 cells, propofol (50 μM) downregulated erastin-induced iron accumulation, excess ROS, and lipid peroxidation by upregulating system Xc-and GPX4.…”

Section: Iron Homeos Ta S Is Ferrop Tos Is and Other G Ener Al Ane ...mentioning

confidence: 99%

“…Ketamine‐induced cognitive impairments in rats were rescued by iron chelator DFP. Conversely, subanesthetic ketamine suppressed chronic restraint stress (CRS) induced ferroptosis by increasing FTH1 and GPX4 levels and decreasingTfr1 levels 104 . Recently, propofol presented a neuroprotective effect on neuronal ferroptosis.…”

Section: Iron Homeostasis Ferroptosis and Other General Anestheticsmentioning

confidence: 99%

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders

Miao,

Han,

Wang

et al. 2024

CNS Neurosci Ther

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In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane‐ and isoflurane‐induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane‐ and isoflurane‐induced neurotoxicity.

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Psychopharmacological Approaches for Neural Plasticity and Neurogenesis in Major Depressive Disorders

Matar,

Serhan,

El Bilani

et al. 2024

Advances in Experimental Medicine and Biology

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Ketamine May Exert Rapid Antidepressant Effects Through Modulation of Neuroplasticity, Autophagy, and Ferroptosis in the Habenular Nucleus

Cited by 15 publications

References 45 publications

The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders

Psychopharmacological Approaches for Neural Plasticity and Neurogenesis in Major Depressive Disorders

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