Abstract
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.
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References
Babayan AH, Kramar EA, Barrett RM, Jafari M, Haettig J, Chen LY et al (2012). Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J Neurosci 32: 12854–12861.
Bi R, Broutman G, Foy MR, Thompson RF, Baudry M (2000). The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci USA 97: 3602–3607.
Briz V, Liu Y, Zhu G, Bi X, Baudry M (2015). A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release. J Cell Biol 210: 1225–1237.
Cazorla M, Premont J, Mann A, Girard N, Kellendonk C, Rognan D (2011). Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. J Clin Invest 121: 1846–1857.
Chan CS, Weeber EJ, Zong L, Fuchs E, Sweatt JD, Davis RL (2006). Beta 1-integrins are required for hippocampal AMPA receptor-dependent synaptic transmission, synaptic plasticity, and working memory. J Neurosci 26: 223–232.
Chen LY, Rex CS, Sanaiha Y, Lynch G, Gall CM (2010). Learning induces neurotrophin signaling at hippocampal synapses. Proc Natl Acad Sci USA 107: 7030–7035.
DeMali KA, Wennerberg K, Burridge K (2003). Integrin signaling to the actin cytoskeleton. Curr Opin Cell Biol 15: 572–582.
Ethell IM, Ethell DW (2007). Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 85: 2813–2823.
Fester L, Rune GM (2015). Sexual neurosteroids and synaptic plasticity in the hippocampus. Brain Res 1621: 162–169.
Foy MR, Xu J, Xie X, Brinton RD, Thompson RF, Berger TW (1999). 17Beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. J Neurophysiol 81: 925–929.
Hara Y, Waters EM, McEwen BS, Morrison JH (2015). Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol Rev 95: 785–807.
Hoetzer GL, Stauffer BL, Irmiger HM, Ng M, Smith DT, DeSouza CA (2003). Acute and chronic effects of oestrogen on endothelial tissue-type plasminogen activator release in postmenopausal women. J Physiol 551: 721–728.
Hoffman KB, Martinez J, Lynch G (1998). Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation? Brain Res 811: 29–33.
Kramar EA, Chen LY, Brandon NJ, Rex CS, Liu F, Gall CM et al (2009). Cytoskeletal changes underlie estrogen's acute effects on synaptic transmission and plasticity. J Neurosci 29: 12982–12993.
Kramar EA, Lin B, Rex CS, Gall CM, Lynch G (2006). Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci USA 103: 5579–5584.
Kumar A, Bean LA, Rani A, Jackson T, Foster TC (2015). Contribution of estrogen receptor subtypes, ERalpha, ERbeta, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice. Hippocampus 25: 1556–1566.
Leranth C, Shanabrough M, Horvath TL (2000). Hormonal regulation of hippocampal spine synapse density involves subcortical mediation. Neuroscience 101: 349–356.
Luine VN, Frankfurt M (2012). Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density. Front Neuroendocrinol 33: 388–402.
Meng R, Tang HY, Westfall J, London D, Cao JH, Mousa SA et al (2011). Crosstalk between integrin alphavbeta3 and estrogen receptor-alpha is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One 6: e27547.
Merlo S, Sortino MA (2012). Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation. Mol Cell Neurosci 49: 423–429.
Miranti CK, Brugge JS (2002). Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4: 83–90.
Moraes J, Assreuy J, Canetti C, Barja-Fidalgo C (2010). Leukotriene B4 mediates vascular smooth muscle cell migration through alphavbeta3 integrin transactivation. Atherosclerosis 212: 406–413.
Mortillo S, Elste A, Ge Y, Patil SB, Hsiao K, Huntley GW et al (2012). Compensatory redistribution of neuroligins and N-cadherin following deletion of synaptic beta1-integrin. J Comp Neurol 520: 2041–2052.
Mukai H, Tsurugizawa T, Murakami G, Kominami S, Ishii H, Ogiue-Ikeda M et al (2007). Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons. J Neurochem 100: 950–967.
Munger JS, Sheppard D (2011). Cross talk among TGF-beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol 3: a005017.
Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J et al (2006). Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26: 1923–1934.
Ni H, Li A, Simonsen N, Wilkins JA (1998). Integrin activation by dithiothreitol or Mn2+ induces a ligand-occupied conformation and exposure of a novel NH2-terminal regulatory site on the beta1 integrin chain. J Biol Chem 273: 7981–7987.
Oberlander JG, Woolley CS (2016). 17Beta-estradiol acutely potentiates glutamatergic synaptic transmission in the hippocampus through distinct mechanisms in males and females. J Neurosci 36: 2677–2690.
Ooishi Y, Kawato S, Hojo Y, Hatanaka Y, Higo S, Murakami G et al (2012). Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol 131: 37–51.
Ortega-Carrion A, Feo-Lucas L, Vincente-Manzanares M (2015) Cell migrationIn: Bradshaw RA, Stahl PD (eds) Encyclopedia of Cell Biology Vol 2. Academic Press: New York, NY. pp 720–730.
Panja D, Bramham CR (2014). BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology 76 (Part C): 664–676.
Puehringer D, Orel N, Luningschror P, Subramanian N, Herrmann T, Chao MV et al (2013). EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons. Nat Neurosci 16: 407–415.
Rajagopal R, Chao MV (2006). A role for Fyn in Trk receptor transactivation by G-protein-coupled receptor signaling. Mol Cell Neurosci 33: 36–46.
Rantamaki T, Vesa L, Antila H, Di Lieto A, Tammela P, Schmitt A et al (2011). Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade. PLoS One 6: e20567.
Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM et al (2009). Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 186: 85–97.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007). Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27: 3017–3029.
Samarajeewa A, Goldemann L, Vasefi MS, Ahmed N, Gondora N, Khanderia C et al (2014). 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation. Front Behav Neurosci 8: 391.
Seese RR, Babayan AH, Katz AM, Cox CD, Lauterborn JC, Lynch G et al (2012). LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knock-out mice. J Neurosci 32: 7403–7413.
Seese RR, Chen LY, Cox CD, Schulz D, Babayan AH, Bunney WE et al (2013). Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. J Neurosci 33: 13441–13448.
Shelton DL, Sutherland J, Gripp J, Camerato T, Armanini MP, Phillips HS et al (1995). Human Trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesions. J Neurosci 15: 477–491.
Simmons DA, Belichenko NP, Yang T, Condon C, Monbureau M, Shamloo M et al (2013). A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington’s disease. J Neurosci 33: 18712–18727.
Smejkalova T, Woolley CS (2010). Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism. J Neurosci 30: 16137–16148.
Spencer JL, Waters EM, Romeo RD, Wood GE, Milner TA, McEwen BS (2008). Uncovering the mechanisms of estrogen effects on hippocampal function. Front Neuroendocrinol 29: 219–237.
Steffensen SC, Jones MD, Hales K, Allison DW (2006). Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors. Hippocampus 16: 1080–1090.
Trieu BH, Kramar EA, Cox CD, Jia Y, Wang W, Gall CM et al (2015). Pronounced differences in signal processing and synaptic plasticity between piriform-hippocampal network stages: a prominent role for adenosine. J Physiol 593: 2889–2907.
Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ et al (1996). Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87: 1317–1326.
Tsilibary E, Tzinia A, Radenovic L, Stamenkovic V, Lebitko T, Mucha M et al (2014). Neural ECM proteases in learning and synaptic plasticity. Prog Brain Res 214: 135–157.
Vierk R, Glassmeier G, Zhou L, Brandt N, Fester L, Dudzinski D (2012). Aromatase inhibition abolishes LTP generation in female but not in male mice. J Neurosci 32: 8116–8126.
Wang XB, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW (2008). Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci USA 105: 19520–19525.
Yuen GS, McEwen BS, Akama KT (2011). LIM kinase mediates estrogen action on the actin depolymerization factor Cofilin. Brain Res 1379: 44–52.
Acknowledgements
We thank Dr Ivan Soltesz for providing CaMKII-Cre mice used for generating the β1 cKOs, Dr Moses Chao for information on TrkB antagonists, and Dr Julie Lauterborn for comments on the manuscript.
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Wang, W., Kantorovich, S., Babayan, A. et al. Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function. Neuropsychopharmacol 41, 2723–2732 (2016). https://doi.org/10.1038/npp.2016.83
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DOI: https://doi.org/10.1038/npp.2016.83
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