Estrogen-induced signaling attenuates soluble Aβ peptide-mediated dysfunction of pathways in synaptic plasticity.
Neuromodulation of synaptic plasticity by 17β-estradiol (E2) is thought to influence information processing and storage in the cortex and hippocampus. Because E2 rapidly affects cortical memory and synaptic plasticity, we examined its effects on phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) [AMPA-type glutamate receptor subunit 1 (GluR1 subunit)], all of which are important for the induction and maintenance of synaptic plasticity and memory. Acute E2 treatment resulted in an increased temporal and spatial phosphorylation pattern of CaMKII, ERK, and AMPAR (GluR1 subunit). By using inhibitors, we were able to attribute GluR1 phosphorylation to CaMKII at serine 831, and we also found that E2 treatment increased GluR1 insertion into the surface membrane. Because soluble amyloid-beta (Aβ) oligomers inhibit CaMKII and ERK activation, which is necessary for synaptic plasticity, we also tested E2's ability to ameliorate Aβ-induced dysfunction of synaptic plasticity. We found that estrogen treatment in neuronal culture, slice culture, and in vivo, ameliorated Aβ oligomer-induced inhibition of CaMKII, ERK, and AMPAR phosphorylation, and also ameliorated the Aβ oligomer-induced reduction of dendritic spine density in a CaMKII-dependent manner. These phosphorylation events are correlated with the early stage of inhibitory avoidance learning, and our data show that E2 improved inhibitory avoidance memory deficits in animals treated with soluble Aβ oligomers. This study identifies E2-induced signaling that attenuates soluble Aβ peptide-mediated dysfunction of pathways in synaptic plasticity.
Department of Pharmacology & Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
Shaun M
SM
Logan
Saumyendra N
SN
Sarkar
Zhang
Z
Zhang
James W
JW
Simpkins
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D009473:Neuronal Plasticity / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D004967:Estrogens; D004958:Estradiol
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