Intriguing roles of hippocampus-synthesized 17β-estradiol in the modulation of hippocampal synaptic plasticity.

Accumulated studies have shown that 17β-estradiol (E2) can be de novo synthesized in the hippocampus, and its role in the regulation of hippocampal synaptic plasticity, which is the basis of learning and memory, has long been exploring. Steroidogenic enzymes (e.g., aromatase) that are essential to the hippocampus-synthesized synthesis of E2 have been detected in the hippocampus. Inhibition of E2 synthesis by aromatase inhibitors significantly reduces the density of hippocampal spine synapses, levels of some synaptic proteins such as spinopholin and synaptophysin. Moreover, the electrophysiological properties of hippocampal neurons are also changed in response to this inhibition. The influences of gonadal and hippocampal E2 on synaptic plasticity may exist some differences, since some reports showed that gonadal (or circulating) estrogens have no obvious effects in the modulation of hippocampal synaptic proteins as evidenced in some ovariectomized animals and postmenopausal women who suffered from Alzheimer's disease (AD). These evidences leads to a hypothesis that hippocampal E2 may play a more important role in modulation of synaptic plasticity than gonadal E2. The signaling pathways, whereby hippocampal E2 modulates synaptic plasticity, insist of classical chronic genomic pathway and rapid nongenomic pathway, which mediated by nonnuclear estrogen receptor (GPER) and/or nuclear or nonnuclear estrogen receptors, which require coactivators for their transcription activity. Among which steroid receptor coactivator-1 (SRC-1) is the predominant coactivator p160 family members in the brain. Several clues have shown that SRC-1 is expressed in hippocampus and is highly correlated with some key synaptic proteins developmentally or after orchidectomy but not ovariectomy, indicating SRC-1 may be regulated by hippocampus-synthesized E2 and profoundly involved in the mediation of hippocampal E2 regulation of hippocampal synaptic plasticity. Further studies about the exact roles of hippocampus-synthesized E2 and therefore SRC-1 are urgently needed in order to facilitate our understanding of hippocampal E2, which will be very important to the development of novel strategies of estrogen replacement therapy against neurodegenerative deficits such as Alzheimer's disease (AD).