For all figures p-values are as follows ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. All statistics were performed in Graphpad Prism. We thank Rylan Larsen and Matt Judson for critical readings of the manuscript, Paul Manis for experimental advice, Yong-hui Jiang for his generous donation of C57BL/6J Ube3a-deficient mutant mice and Kristen Phend for histological support. Imaging was supported by the Confocal and Multiphoton Imaging Core
of NINDS Center Grant P30 NS045892 and NICHD Center Grant P30 HD03110. M.L.W was supported by a Neurobiology Research Training Grant from NINDS (5T32NS007431) and a National Research Service Award from NINDS (1F31NS077847). R.J.W. was supported by NINDS Ruxolitinib cell line (5R01NS035527). B.D.P was supported by the Angelman Syndrome Foundation, the Simons Foundation, the National Eye Institute (R01EY018323), and the National Institute of Mental Health (1R01MH093372). “
“Estrogens influence hippocampal function through multiple mechanisms with time
courses ranging from minutes to days. Recent recognition that a key estrogen, GW786034 supplier 17β-estradiol (E2), is produced as a neurosteroid in the brains of both males and females has fueled a resurgence of interest in acute nongenomic estrogen signaling (Woolley, 2007). Many hippocampal neurons express the E2-synthesizing enzyme P450 aromatase (Hojo et al., 2004), which could provide a source of locally generated E2 to acutely modulate synaptic function in vivo. E2 applied to hippocampal slices rapidly potentiates synaptically evoked field excitatory postsynaptic potentials (EPSPs) in the CA1 region (Teyler et al., 1980), as well as intracellularly recorded EPSPs (Wong and Moss, 1992) and excitatory postsynaptic currents (EPSCs) (Smejkalova and Woolley, 2010) in CA1 pyramidal cells. On the one hand, E2 appears to act on excitatory synapses through the β form of the classical estrogen receptor (ERβ). ERβ agonists rapidly increase AMPA receptor (AMPAR)-mediated field EPSPs (Kramár et al., 2009) and unless EPSCs (Smejkalova and Woolley, 2010), whereas ERα agonists do not affect AMPAR-mediated responses. On the other hand, E2-induced potentiation of field EPSPs is reduced in ERα knockout
compared to wild-type mice (Fugger et al., 2001), suggesting a more complex action of E2. One possibility is that E2 acutely potentiates excitatory synapses via ERβ and simultaneously suppresses inhibitory synapses via ERα. To investigate acute modulation of inhibitory synapses, we recorded GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells with application of E2 to hippocampal slices from adult female rats. We found that, in a subset of cells, E2 rapidly suppresses IPSCs. Subsequent studies indicated that E2-induced IPSC suppression depends on ERα- and mGluR1-dependent mobilization of endocannabinoids to decrease the probability of GABA release from CB1R-containing inhibitory synaptic inputs. Additionally, E2-induced suppression of IPSCs occurred in females but not in males.