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Event: 2078
Key Event Title
Loss of drebrin
Short name
Biological Context
Level of Biological Organization |
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Cellular |
Cell term
Cell term |
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neuron |
Organ term
Organ term |
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brain |
Key Event Components
Process | Object | Action |
---|---|---|
postsynaptic actin cytoskeleton organization | drebrin | decreased |
dendritic spine morphogenesis | actin cytoskeleton | decreased |
regulation of actin-dependent ATPase activity | actin cytoskeleton | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
IGR binding leads to impairment of learning and memory (via loss of drebrin) | KeyEvent | Shihori Tanabe (send email) | Under development: Not open for comment. Do not cite | Under Development |
elavl3, sox10, mbp induced neuronal effects | KeyEvent | Donggon Yoo (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Human, rat, mouse | Human, rat, mouse | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
During brain development, adulthood and aging | High |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Key Event Description
Glutamate induces the translocation of drebrin from dendritic spines to dendritic shafts, as reported in mature cultured rodent neurons and human iPS-derived neurons (Sekino et al. 2006; Mizui et al.2014; Lin et al. 2023). This "drebrin exodus" is a physiological process occurring at the initiation of synaptic plasticity, observed immediately after excitatory postsynapses receive electrical or chemical stimulation that induces long-term potentiation (LTP) or long-term depression (LTD) .
NMDA-induced excitotoxicity leads to the degradation of drebrin in mature cultured neurons from rodent hippocampus and cortex. This process is triggered by calcium influx and mediated by calpain activity.
Drebrin is an evolutionarily conserved actin-binding protein localized in dendritic spines. Overexpression of drebrin A in neurons enlarges dendritic spines and reduces spine motility, whereas down-regulation of drebrin A decreases the density and width of dendritic spines and inhibits the synaptic clustering of NMDA receptors (NMDARs).
Drebrin stabilizes actin filaments and plays a pivotal role in dendritic spine morphogenesis (Hayashi and Shirao, 1999; Takahashi et al., 2003; Takahashi et al., 2006).
During the initial stages of synaptic plasticity (either LTP or LTD), Ca²⁺ influx through NMDA receptors triggers the translocation of drebrin from dendritic spines (Sekino et al., 2006).
Moreover, prolonged NMDA-induced excitotoxicity results in calpain-mediated degradation of drebrin both in vitro and in vivo.
How It Is Measured or Detected
Loss of drebrin from dendritic spines can be detected by immunocytochemistry, ELISA or or Western blotting in cultured human and rodent neurons and brain tissues (Counts et al., 2006; Ishizuka et al., 2014).
The twenty-one-day primary cultured neurons were prepared using frozen stock of dissociated hippocampal neurons (Koganezawa et al, 2023; Hanamura et al 2019). In brief, cells were cultured in multi well microplates with defined medium. Using cryopreservednhippocampal neurons reduces animal use.
For enzyme-linked immunoassay, after the incubation of chemicals the extracts of neurons were quantified using ELISA kit for drebrin (ALzMEd, Inc.),
For immunocytochemistry, the cultured neurons were incubated with chemicals for 1 hour. After fixation, cultured neurons were immunostained with anti-drebrin and anti-MAP2 antibodies. The cluster density of drebrin along the dendrites was automatically quantified using high content analysis instruments (Hanamura et al, 2019, Mitsuoka et al, 2019).
Domain of Applicability
This KE applies to mammals of both sexes, during neuronal development at any life stage (both immature and adult nervous system).
References
Chronological order : newest first
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Koganezawa, N., Roppongi, R.T.,Sekino, Y., Tsutsui, I., Higa, A.,Shirao, T. Easy and Reproducible Low-Density Primary Culture using Frozen Stock of Embryonic Hippocampal Neurons. J. Vis. Exp. (191), e64872, doi:10.3791/64872 (2023).
Mitsuoka T, Hanamura K, Koganezawa N, Kikura-Hanajiri R, Sekino Y, Shirao T. “Assessment of NMDA receptor inhibition of phencyclidine analogues using a high-throughput drebrin immunocytochemical assay” J Pharmacol Toxicol Methods 2019 May 10:106583. doi: 10.1016/j.vascn.2019.106583.
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Puspitasari A, Koganezawa N, Ishizuka Y, Kojima N, Tanaka N, Nakano T, Shirao T. X Irradiation Induces Acute Cognitive Decline via Transient Synaptic Dysfunction. Radiat Res. 2016 Apr;185(4):423-30. doi: 10.1667/RR14236.1. Epub 2016 Mar 29. PMID: 27023259.
Chimura T, Launey T, Yoshida N (2015) Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo. PLoS ONE 10(4): e0125119. doi:10.1371/journal.pone.0125119
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Ishizuka Y, Shimizu H, Takagi E, Kato M, Yamagata H, Mikuni M, Shirao T. Histone deacetylase mediates the decrease in drebrin cluster density induced by amyloid beta oligomers. Neurochem Int. 2014 Oct;76:114-21. doi: 10.1016/j.neuint.2014.07.005. Epub 2014 Jul 21. PMID: 25058791.
Mizui T, Sekino Y, Yamazaki H, Ishizuka Y, Takahashi H, Kojima N, Kojima M, Shirao T. Myosin II ATPase activity mediates the long-term potentiation-induced exodus of stable F-actin bound by drebrin A from dendritic spines. PLoS One. 2014 Jan 22;9(1):e85367. doi: 10.1371/journal.pone.0085367. PMID: 24465547; PMCID: PMC3899004.
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Kojima N, Hanamura K, Yamazaki H, Ikeda T, Itohara S, Shirao T. Genetic disruption of the alternative splicing of drebrin gene impairs context-dependent fear learning in adulthood. Neuroscience. 2010 Jan 13;165(1):138-50. doi: 10.1016/j.neuroscience.2009.10.016. Epub 2009 Oct 24. PMID: 19837137.
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