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 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. Specifically, we show that in cortical neurons with reduced dendritic spine density, produced by either ectopically expressing wildtype or mutant Disrupted in Schizophrenia (DISC1) constructs, that acute treatment with 17β-estradiol increased spine density to control levels. Furthermore, 17β-estradiol causes a redistribution of both exogenous and endogenous DISC1, a mechanism whereby DISC1’s inhibitory effects on synapse formation is thought to occur. In addition, we also observe an increased targeting of PSD-95 and kalriin-7, which form a signalsome with DISC1, following 17β-estradiol treatment. Taken together, out data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the bidirectional 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 excitatory synaptic number.