Estrogen's Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function.
Estradiol (E2) perfusion rapidly increases the strength of fast excitatory transmission and facilitates long-term potentiation in the hippocampus, two effects likely related to its memory-enhancing properties. Past studies showed that E2's facilitation of transmission involves activation of RhoA signaling leading to actin polymerization in dendritic spines. Here we report that brief exposure of adult male hippocampal slices to 1 nM E2 increases the percentage of postsynaptic densities associated with high levels of immunoreactivity for activated forms of the BDNF receptor TrkB and β1-integrins, two synaptic receptors that engage actin regulatory RhoA signaling. The effects of E2 on baseline synaptic responses were unaffected by pretreatment with the TrkB-Fc scavenger for extracellular BDNF or TrkB antagonism, but were eliminated by neutralizing antisera for β1-integrins. E2 effects on synaptic responses were also absent in conditional β1-integrin knockouts, and with inhibition of matrix metalloproteinases, extracellular enzymes that generate integrin ligands. We propose that E2, acting through estrogen receptor-β, transactivates synaptic TrkB and β1-integrin, and via mechanisms dependent on integrin activation and signaling, reversibly reorganizes the spine cytoskeleton and thereby enhances synaptic responses in adult hippocampus.
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Weisheng
W
Wang
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Svetlana
S
Kantorovich
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Alex H
AH
Babayan
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Bowen
B
Hou
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.|Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
Christine M
CM
Gall
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.|Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
Gary
G
Lynch
D000818:Animals; D000831:Animals, Newborn; D052117:Benzodioxoles / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
C524478:1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole; C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D004151:Dipeptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D019012:Integrin beta1; D016023:Integrins; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D011960:Receptors, Estrogen; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D051528:Guanylate Kinases