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

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 17βestradiol 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 (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. S. performed all experiments and subsequent analysis. J.M., S.J.M. and P.P. produced or oversaw production of reagents; J.M., N.J.B., P.P. and D.P.S. wrote the manuscript.

Mechanism of saikogenin G against major depressive disorder determined by network pharmacology

“…Several studies have demonstrated that estrogen performs favorable effects in MDD via modulating monoamine neurotransmitters (DA and 5-hydroxytryptamine), inflammatory processes, and dendritic spine number. [50,51] The activation of ERK and PI3K elevates after acute treatment with 17β-estradiol. Estrogen is an important adjunct to antidepressant drug treatments clinically.…”

Developmental effects of constitutive mTORC1 hyperactivity and environmental enrichment on structural synaptic plasticity and behaviour in a rat model of autism spectrum disorder

“…The reliance of exploratory, anxiety and social behaviours on the limbic system (which includes the cingulate gyrus and hippocampus) and related circuits (Eslinger et al, 2021; Martin et al, 2010; Winter et al, 2013) prompted our histochemical investigations of changes in dendritic spine density and morphology, which are known to be altered in human ASD (Erli et al, 2020; Joensuu et al, 2018; Penzes et al, 2011, 2013) and in ASD experimental animal models (Gadad et al, 2013; Peier et al, 2000). Although in vitro evidence suggests an important role of TSC2 protein in governing the dendritic spine morphology and density, in rapamycin‐dependent and rapamycin‐independent ways (Yasuda et al, 2014; Zhou et al, 2006), to the best of our knowledge, the impact of Tsc2 loss‐of‐function on dendritic spine morphology in vivo has been only studied at a single developmental stage of transgenic mice (Meikle et al, 2008; Tavazoie et al, 2005).…”

“…As a neurodevelopmental disorder, ASD is characterized by altered connectivity in the brain, owing to abnormal synapse formation and functional plasticity (Erli et al, 2020; Joensuu et al, 2018; Penzes et al, 2011, 2013). Although the causative role of genetic and environmental factors in ASD is well recognized (Bai et al, 2019; Chaste & Leboyer, 2012; Cheroni et al, 2020; Talkowski et al, 2014; Tseng et al, 2022), the effect of their interaction on the onset and progression of the disease remains elusive.…”