piperidines and batimastat

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.

Topics: Animals; Animals, Newborn; Benzodioxoles; Dipeptides; Disks Large Homolog 4 Protein; Estrogen Receptor Modulators; Estrogens; Excitatory Postsynaptic Potentials; Female; Gene Expression Regulation; Guanylate Kinases; Hippocampus; Integrin beta1; Integrins; Male; Matrix Metalloproteinase Inhibitors; Membrane Proteins; Mice, Knockout; Neurons; Phenylalanine; Piperidines; Pyrazoles; Pyrimidines; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Thiophenes