Progesterone-estrogen interactions in synaptic plasticity and neuroprotection

Abstract

17ß-Estradiol and progesterone exert a number of physiological effects throughout the brain due to interactions with several types of receptors belonging to the traditional family of intracellular hormonal receptors as well as to membrane-bound receptors. In particular, both hormones elicit rapid modifications of neuronal excitability that have been postulated to underlie their effects on synaptic plasticity and learning and memory. Likewise, both hormones have been shown to be neuroprotective under certain conditions, possibly due to the activation of pro-survival pathways and the inhibition of pro-apoptotic cascades. Because of the similarities in their cellular effects, there have been a number of questions raised by numerous observations that progesterone inhibits the effects of estrogen. In this manuscript, we first review the interactions between 17ß-estradiol (E2) and progesterone (P4) in synaptic plasticity, and conclude that, while E2 exerts a clear and important role in long-term potentiation of synaptic transmission in hippocampal neurons, the role of P4 is much less clear, and could be accounted by the direct or indirect regulation of GABAA receptors. We then discuss the neuroprotective roles of both hormones, in particular against excitotoxicity. In this case, the neuroprotective effects of these hormones are very similar to those of the neurotrophic factor BDNF. Interestingly, P4 antagonizes the effects of E2, possibly through the regulation of estrogen receptors or of proteins associated with the receptors or interactions with signaling pathways activated by E2. Overall, this review emphasizes the existence of common molecules and pathways that participate in the regulation of both synaptic plasticity and neurodegeneration.

Figure 1. Schematic representation of the pathways activated by E2 and P4 in neurons

E2 is proposed to activate three types of receptors, i) membrane-bound receptors (ERm) resulting in activation of the src tyrosine kinase and leadong to MAPK/ERK activation. ii) the traditional cytoplasmic receptors, which in conjunction with the steroid receptor coactivator-1 (SRC-1) triggers transcriptional responses, and iii) the GPER receptor, which is localized either in membrane or in the cytoplasm; the functions of this receptor ar still being unraveled and it appears to play a significant role in neuroprotection. P4 is shown to activate i) a membrane bound receptor (mPR) as well as ii) traditional cytoplamc receptors that trigger transcription. Through metabolites such as allopregnanolone, P4 may also activate GABA_A receptors, which induce LTP. Also shown are the structures of E2 and P4 along with the corresponding fluctuations in their plasma levels across the rat estrus cycle.

Figure 2. Schematic illustration of the links between E2 and synaptic plasticity

E2 activation of membrane receptors leads to structural synaptic changes that result in increased synaptic activity and facilitation of LTP induction/consolidation. Part of these effects involve calpain activation via ERK/MAPK-mediated phosphorylation as well as calpain inhibition via PKA-mediated phosphorylation. E2 also regulate actin polymerization via the RhoA-LIMK-cofilin pathway.

Figure 3. Schematic representation of postulated interactions between E2 and P4

Both E2 and P4 trigger calpain activation, presumably through ERK-mediated phosphorylation. In addition, both E2 and P4 increase BDNF expression, which further stimulates calpain activation. These responses are involved in the neuroprotective effects of both E2 and P4. However, P4 is proposed to negatively regulate the stimulatory effects of E2 and BDNF on calpain activation as well as through the destabilization of mRNA for ERβ and BDNF.