Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function

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.

β1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice

“…Nevertheless, more recent reports indicate that both male and female mice use the OFC to update action-outcome expectancies (Swanson et al, 2015;Baltz et al, 2018). Another consideration is that estradiol activates neuronal ␤1-integrins to facilitate synaptic transmission (Wang et al, 2016). Our viral vector strategy reduced, but did not eliminate, ␤1-integrins, leaving open the possibility that higher estradiol levels in females stimulated remaining ␤1-integrins to overcome the behavioral consequences of gene silencing.…”

“…Prior investigations by the Lynch laboratory revealed that the sex hormone estradiol enhances ␤1-integrin-dependent synaptic responses and coactivates the neurotrophin receptor trkB (Wang et al, 2016). This phenomenon could conceivably account for resilience to OFC Itgb1 deficiency in females.…”

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

“…The mice included (1) Munc18-1 heterozygote knockouts (KOs) (Munc18-1 +/− ; a.k.a. STXBP1 from Riken labs) and background strain (C57BL/6N) matched wild types for comparison, and (2) conditional β1-integrin KOs created by crossing mice with floxed β1-integrin exon 3 with mice expressing Crerecombinase under control of the CaMKIIα promoter (Mortillo et al 2012;Wang et al 2016a); in the progeny the expression of Cre by excitatory hippocampal and cortical neurons (Tsien et al 1996) leads to excision of β1 exon 3 and disruption of β1 protein expression beginning at 3 weeks of age. The present studies used β1 KOs at 8 weeks of age.…”

“…We then assessed lppLTP in slices from conditional β1 KO mice. For these studies, mice with floxed β1 exon 3 (B6;129-Itgb1tm1Efu/J strain) were crossed with CaMKIIα-Cre mice (B6.Cg-Tg(Camk2a-cre)T29-firstl/J) to generate KOs with β1 expression depressed in excitatory hippocampal neurons beginning in the third week of life (Wang et al 2016a). The LPP I/O curve in β1 KOs was slightly depressed relative to wild types but this effect did not approach statistical significance (P = 0.17; Fig.…”

17α Estradiol promotes plasticity of spared inputs in the adult amblyopic visual cortex

“…Acute E2 delivered in vivo or ex vivo induces robust spinogenesis in the hippocampus of young adult male and female rats 11,25,69,71 and this effect may be lost with age or following OVX 72 . Brief E2 treatment of hippocampal slices from young males and middle-aged OVX females induces an increase in F-actin, without a change in PSD95 puncta number 14,73 . Similarly, Golgi stains of mouse hippocampus from OVX females (P42) reveal an increase in the number of large, mushroom-type spines following repetitive E2 treatment (1x day / 5 days 74 ).…”