, 2007), which are also those that contain CB1Rs (Katona et al., 1999). Whether sex differences in pre- and/or postsynaptic extranuclear ERα signaling (Romeo et al., 2005) contribute

to the lack of E2 effect in males remains to be determined. Comparing the levels, distribution, and function of each step in the pathway(s) leading from E2 activation of extranuclear ERα to modulation of GABA release in both males and females may point to which of the many signaling pathways acutely activated by E2 are relevant to acute suppression of inhibitory synaptic transmission. E2 is well known to influence hippocampal functions such as memory and affective behaviors that differ between the sexes (Gillies and McArthur, 2010), as well as PI3K inhibitor neurological disorders that involve the hippocampus such as temporal lobe epilepsy (Guille et al., 2008). Most behavioral studies have examined effects Lumacaftor of E2 in females and on a timescale corresponding to ovarian E2 fluctuations, which is much slower than the acute suppression of inhibition that we report

here. In addition, the concentrations of E2 required for acute suppression of IPSCs, 10–100 nM, are higher than peak circulating levels (∼100 pM), indicating that inhibitory synapses are likely to be protected from acute modulation by relatively slow and low amplitude fluctuations in ovarian E2. In contrast, neurosteroid E2 is reportedly 5–10 nM on average (Hojo et al., 2009), probably higher near sites of aromatase activity, and its synthesis may be activity dependent (Hojo et al., 2004). Thus, neurosteroid E2 could provide a localized source of E2 to acutely modulate synaptic inhibition in vivo. A better understanding of sex-specific synaptic modulation in the hippocampus and how E2 acutely regulates endocannabinoid tone in females may point to targets for novel therapies to combat neurological or mental health disorders that differ between the sexes. Animals were adult female (ovariectomized) or male (castrated or gonadally intact)

rats. Using standard methods, hippocampal slices were prepared and whole-cell medroxyprogesterone voltage-clamp recordings were made at 34°C–35°C with a K-gluconate-based internal solution. For more information, see Supplemental Experimental Procedures available online. Of note, E2 modulation of IPSCs was never observed when recording with a CsCl-based internal solution, possibly owing to interference with postsynaptic G protein-coupled signaling. All drugs used are noted in the text, including concentrations. Data are reported as mean ± SEM. We thank Indira Raman for many helpful discussions. This work was supported by R01 NS037324 (C.S.W.). “
“Responses of cells in visual cortex have generally been probed under conditions of passive viewing.