Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders.

Dendritic Spines Depressive Disorder, Major Estradiol / pharmacology Estrogens Humans Synapses

Journal

Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664

Informations de publication

Date de publication:
21 01 2020
Historique:
received: 02 05 2018
accepted: 28 11 2019
revised: 26 11 2019
entrez: 19 2 2020
pubmed: 19 2 2020
medline: 22 6 2021
Statut: epublish

Résumé

Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia 1 (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.

Identifiants

DOI: 10.1038/s41398-020-0682-4 PMID: 32066698 PMC: PMC7026123
pubmed: 32066698
doi: 10.1038/s41398-020-0682-4
pii: 10.1038/s41398-020-0682-4
pmc: PMC7026123
doi:

Substances chimiques

Estrogens 0
Estradiol 4TI98Z838E

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

16

Subventions

Organisme : RCUK | Medical Research Council (MRC)
ID : MR/L021064/1
Pays : International
Organisme : NINDS NIH HHS
ID : R21 NS103865
Pays : United States
Organisme : Royal Society
ID : RG130856
Pays : International
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/M503356/1
Pays : International
Organisme : NIMH NIH HHS
ID : R01 MH097216
Pays : United States
Organisme : Medical Research Council
ID : MR/N026063/1
Pays : United Kingdom
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : R01MH097216
Pays : International
Organisme : NIMH NIH HHS
ID : R01 MH071316
Pays : United States
Organisme : National Alliance for Research on Schizophrenia and Depression (NARSAD)
ID : 25957
Pays : International
Organisme : NIMH NIH HHS
ID : R01 MH118263
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS087662
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS081986
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : R01MH071316
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS101888
Pays : United States

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Auteurs

Filippo Erli (F)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.

Alish B Palmos (AB)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.

Pooja Raval (P)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.

Jayanta Mukherjee (J)

AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, UK.

Katherine J Sellers (KJ)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.

Nicholas J F Gatford (NJF)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.

Stephen J Moss (SJ)

AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, UK.

Nicholas J Brandon (NJ)

AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, UK.
Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, UK.

Peter Penzes (P)

Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Centre for Autism and Neurodevelopment, Northwestern University, Chicago, IL, USA.

Deepak P Srivastava (DP)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK. deepak.srivastava@kcl.ac.uk.
Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. deepak.srivastava@kcl.ac.uk.
MRC Centre for Neurodevelopmental Disorders, King's College London, London, SE1 1UL, UK. deepak.srivastava@kcl.ac.uk.
ORCID: 0000-0001-6512-9065

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Classifications MeSH

questionsmedicales.fr › Cellules › Neurones › Dendrites › Épines dendritiques › Estradiol reverses excitatory synapse loss in...
questionsmedicales.fr › Troubles mentaux › Troubles de l'humeur › Trouble dépressif › Trouble dépressif majeur › Estradiol reverses excitatory synapse loss in...
questionsmedicales.fr › Hormones gonadiques › Hormones sexuelles stéroïdiennes › Congénères de l'oestradiol › Oestradiol › Estradiol reverses excitatory synapse loss in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Hormones › Oestrogènes › Estradiol reverses excitatory synapse loss in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Estradiol reverses excitatory synapse loss in...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Synapses › Estradiol reverses excitatory synapse loss in...