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

Filippo Erli, Alish B. Palmos, Pooja Raval, Jayanta Mukherjee, Katherine J. Sellers, Nicholas J.F. Gatford, Stephen J. Moss, Nicholas J. Brandon, Peter Penzes, Deepak P. Srivastava*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number16
JournalTranslational psychiatry
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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    Erli, F., Palmos, A. B., Raval, P., Mukherjee, J., Sellers, K. J., Gatford, N. J. F., Moss, S. J., Brandon, N. J., Penzes, P., & Srivastava, D. P. (2020). Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders. Translational psychiatry, 10(1), [16]. https://doi.org/10.1038/s41398-020-0682-4