Estrogen-induced signaling links structural and functional synaptic plasticity.

摘要

It is well documented that of its many roles, estrogen can acutely alter the intrinsic and synaptic physiology of neuronal circuits in various regions of the brain. However, the molecular and cellular mechanisms by which estrogen couples electrophysiology to plasticity and memory are still not fully understood. Our data suggests a new possible mechanism by which estrogen, via L-type voltage-gated calcium channel (L-type VGCC) potentiation, modulates memory related synaptic plasticity.;The rapid onset of 17beta-estradiol (E2) action (less than one second) supports the hypothesis that E2 directly interacts with the channel protein. Several techniques allowed us to confirm that not only does E2 bind with high affinity to the L-type VGCC, but that it binds at a domain that overlaps with the dihydropyridine (DHP) site.;Further, to determine whether E2-induced biochemical signaling mechanistically links synaptic plasticity, we studied the phosphorylation patterns of structural and functional plasticity related proteins (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR], AMPA-type glutamate receptor subunit 1 [GluR1], calcium/calmodulin-dependent protein kinase II [CaMKII], and extracellular signal-related kinase [ERK]). E2 rapidly increased phosphorylation of CaMKII, ERK, and AMPAR in primary cortical neurons and in vivo in the cortex. The CaMKII inhibitor (KN-93) decreased phosphorylation levels of GluR1 in primary cortical neurons. We also determined that soluble amyloid-beta (Abeta) 1-42 oligomers abrogated, while E2 ameliorated phosphorylation of GluR1 at its CaMKII site. Abeta treatment also inhibited GluR1 trafficking, but E2 prevented this inhibition. Due to our observation that E2 treatment rapidly increased spine number and ameliorated Abeta-induced spine loss, we concluded that estrogen-induced signaling does in fact mechanistically link structural and functional plasticity.;In comparison with the cortical data (in vitro and in vivo), we found that E2 treatment in hippocampal slice culture ameliorated Abeta oligomer-induced inhibition of CaMKII and AMPAR phosphorylation, reduction of dendritic spine density, and abnormalities in LTP-induced spine growth. Taken together, these results suggest that acute estrogen treatment has the potential to prevent Abeta oligomer-induced synaptic dysfunction.