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

BioRxiv : the Preprint Server for Biology
Filippo ErliDeepak P Srivastava


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 SCZ and MDD using in vivo and in vitro systems have further 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 these beneficial effects are exerted by 17β-estradiol is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore excitatory synapses 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 enr...Continue Reading

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