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Event: 2078

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Loss of drebrin

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Loss of drebrin
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
neuron

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
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

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Human, rat, mouse Human, rat, mouse High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During brain development, adulthood and aging High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

This KE applies to mammals of both sexes, during neuronal development at any life stage (both immature and adult nervous system).  

References

List of the literature that was cited for this KE description. More help

Chronological order : newest first

Yamazaki H, Koganezawa N, Yokoo H, Sekino Y, Shirao T. Super-resolution imaging reveals the relationship between CaMKIIβ and drebrin within dendritic spines. Neurosci Res. 2024 Feb;199:30-35. doi: 10.1016/j.neures.2023.08.002. Epub 2023 Sep 1. PMID: 37659612.

Kajita Y, Kojima N, Shirao T. A lack of drebrin causes olfactory impairment. Brain Behav. 2024 Jan;14(1):e3354. doi: 10.1002/brb3.3354. PMID: 38376048; PMCID: PMC10757890.

Song L, Chen H, Qiao D, Zhang B, Guo F, Zhang Y, Wang C, Li S, Cui H. ZIP9 mediates the effects of DHT on learning, memory and hippocampal synaptic plasticity of male Tfm and APP/PS1 mice. Front Endocrinol (Lausanne). 2023 May 25;14:1139874. doi: 10.3389/fendo.2023.1139874. PMID: 37305050; PMCID: PMC10248430.

Lin W, Shiomoto S, Yamada S, Watanabe H, Kawashima Y, Eguchi Y, Muramatsu K, Sekino Y. Dendritic spine formation and synapse maturation in transcription factor-induced human iPSC-derived neurons. iScience. 2023 Feb 27;26(4):106285. doi: 10.1016/j.isci.2023.106285. Erratum in: iScience. 2023 Jul 20;26(8):107423. doi: 10.1016/j.isci.2023.107423. PMID: 37034988; PMCID: PMC10073939.

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.

Hanamura K, Koganezawa N, Kamiyama K, Tanaka N, Oka T, Yamamura M, Sekino Y, Shirao T. “High-content imaging analysis for detecting the loss of drebrin clusters along dendrites in cultured hippocampal neurons.” J Pharmacol Toxicol Methods. 2018 Sep - Oct;99:106607. doi: 10.1016/j.vascn.2019.106607.

Yamazaki H, Sasagawa Y, Yamamoto H, Bito H, Shirao T. CaMKIIβ is localized in dendritic spines as both drebrin-dependent and drebrin-independent pools. J Neurochem. 2018 Jul;146(2):145-159. doi: 10.1111/jnc.14449. Epub 2018 Jun 11. PMID: 29675826; PMCID: PMC6099455.

Cho C, MacDonald R, Shang J, Cho MJ, Chalifour LE, Paudel HK. Early growth response-1-mediated down-regulation of drebrin correlates with loss of dendritic spines. J Neurochem. 2017 Jul;142(1):56-73. doi: 10.1111/jnc.14031. Epub 2017 Apr 26. PMID: 28369888.

Liu Y, Xu YF, Zhang L, Huang L, Yu P, Zhu H, Deng W, Qin C. Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (ΔE9) mice. CNS Neurosci Ther. 2017 Jul;23(7):590-604. doi: 10.1111/cns.12706. Epub 2017 Jun 8. PMID: 28597477; PMCID: PMC6492767.

Sekino Y, Koganezawa N, Mizui T, Shirao T. Role of Drebrin in Synaptic Plasticity. Adv Exp Med Biol. 2017;1006:183-201. doi: 10.1007/978-4-431-56550-5_11. PMID: 28865021.

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

Jung G, Kim EJ, Cicvaric A, Sase S, Gröger M, Höger H, Sialana FJ, Berger J, Monje FJ, Lubec G. Drebrin depletion alters neurotransmitter receptor levels in protein complexes, dendritic spine morphogenesis and memory-related synaptic plasticity in the mouse hippocampus. J Neurochem. 2015 Jul;134(2):327-39. doi: 10.1111/jnc.13119. Epub 2015 Apr 29. PMID: 25865831.

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.

Roppongi RT, Kojima N, Hanamura K, Yamazaki H, Shirao T. Selective reduction of drebrin and actin in dendritic spines of hippocampal neurons by activation of 5-HT(2A) receptors. Neurosci Lett. 2013 Jun 28;547:76-81. doi: 10.1016/j.neulet.2013.04.061. Epub 2013 May 14. PMID: 23684573.

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.

Aoki C, Kojima N, Sabaliauskas N, Shah L, Ahmed TH, Oakford J, Ahmed T, Yamazaki H, Hanamura K, Shirao T. Drebrin a knockout eliminates the rapid form of homeostatic synaptic plasticity at excitatory synapses of intact adult cerebral cortex. J Comp Neurol. 2009 Nov 1;517(1):105-21. doi: 10.1002/cne.22137. PMID: 19711416; PMCID: PMC2839874.

Ivanov A, Esclapez M, Ferhat L. Role of drebrin A in dendritic spine plasticity and synaptic function: Implications in neurological disorders. Commun Integr Biol. 2009 May;2(3):268-70. doi: 10.4161/cib.2.3.8166. PMID: 19641748; PMCID: PMC2717538.

Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):796-807. doi: 10.1523/JNEUROSCI.3501-06.2007. PMID: 17251419; PMCID: PMC6672917.

Takahashi H, Mizui T, Shirao T. Down-regulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones. J Neurochem. 2006 Apr;97 Suppl 1:110-5. doi: 10.1111/j.1471-4159.2005.03536.x. PMID: 16635259.

Sekino Y, Tanaka S, Hanamura K, Yamazaki H, Sasagawa Y, Xue Y, Hayashi K, Shirao T. (2006)  Activation of N-methyl-D-aspartate receptor induces a shift of drebrin distribution: disappearance from dendritic spines and appearance in dendritic shafts. Mol Cell Neurosci.Mar;31(3):493-504. doi: 10.1016/j.mcn.2005.11.003. Epub 2005 Dec 20. PMID: 16368245.

Kobayashi R, Sekino Y, Shirao T, Tanaka S, Ogura T, Inada K, Saji M. Antisense knockdown of drebrin A, a dendritic spine protein, causes stronger preference, impaired pre-pulse inhibition, and an increased sensitivity to psychostimulant. Neurosci Res. 2004 Jun;49(2):205-17. doi: 10.1016/j.neures.2004.02.014. PMID: 15140563.

Aoki C, Fujisawa S, Mahadomrongkul V, Shah PJ, Nader K, Erisir A. NMDA receptor blockade in intact adult cortex increases trafficking of NR2A subunits into spines, postsynaptic densities, and axon terminals. Brain Res. 2003 Feb 14;963(1-2):139-49. doi: 10.1016/s0006-8993(02)03962-8. PMID: 12560119.

Shim KS, Lubec G. Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer's disease and Down syndrome. Neurosci Lett. 2002 May 24;324(3):209-12. doi: 10.1016/s0304-3940(02)00210-0. PMID: 12009525.

Tomidokoro Y, Harigaya Y, Matsubara E, Ikeda M, Kawarabayashi T, Shirao T, Ishiguro K, Okamoto K, Younkin SG, Shoji M. Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J Pathol. 2001 Aug;194(4):500-6. doi: 10.1002/path.897. PMID: 11523060.

Harigaya Y, Shoji M, Shirao T, Hirai S. Disappearance of actin-binding protein, drebrin, from hippocampal synapses in Alzheimer's disease. J Neurosci Res. 1996 Jan 1;43(1):87-92. doi: 10.1002/jnr.490430111. PMID: 8838578.