Subsequent work is necessary to further understand the mechanisms by which TA-CA1 synapses contribute to heightened hippocampal dependent learning with E2 replacement. Acknowledgements: We thank Shawn Williams and Ed Phillips in the high resolution imaging facility for assistance with confocal microscopy. Grant Sponsor: NIH NIMH Grant number: MH 82304 to LLM, Evelyn F. our previous findings at SC-CA1 synapses. However, in contrast to SC-CA1 synapses, AMPAR transmission at TA-CA1 synapses is usually significantly increased, and there is no effect on the LTP magnitude. Pharmacological blockade of GluN2B-containing NMDARs or ERK activation, which occurs downstream of synaptic but not extrasynaptic GluN2B-containing NMDARs, attenuates the LTP magnitude only in slices from E2-treated rats. These data show that E2 recruits a causal role for GluN2B-containing NMDARs and ERK signaling in the induction of LTP, cellular mechanisms not required for LTP induction at TA-CA1 synapses in vehicle-treated ovariectomized female rats. strong class=”kwd-title” Keywords: Estrogen, hippocampus, NMDA receptors, females, spine density Introduction E2 replacement reverses deficits in working, verbal, and spatial memory in naturally and surgically menopausal women (Henderson, 2009; Compound 401 Phillips and Sherwin, 1992; Rocca et al., 2011; Zec and Trivedi, 2002), and enhances many forms of hippocampus-dependent learning and memory in female mice, rats, and non-human primates (Frick et al., 2002; Gibbs, 1999; Gresack and Frick, 2006; Rapp et al., 2003; Vedder et al., 2013). In defining the mechanisms contributing to the E2-enhanced learning and memory, much focus has been placed on functional and morphological changes occurring at CA3 Schaffer collateral (SC)-CA1 synapses. At proestrus in ovary intact female rats, or in ovariectomized (OVX) rats treated with exogenous E2 at proestrous-like levels, Compound 401 CA1 pyramidal cell dendritic spine density, current mediated by GluN2B-containing NMDARs, the NMDAR:AMPAR ratio, and the magnitude of LTP at SC-CA1 synapses are increased Rabbit polyclonal to HOMER1 (Cordoba Montoya and Carrer, 1997; Gould et al., 1990; Smith and McMahon, 2005; Smith and McMahon, 2006; Snyder et al., 2011; Warren et al., 1995; Woolley et al., 1990; Woolley and McEwen, 1994). The increase in current carried by GluN2B-containing NMDARs, likely due to increased synaptically located NMDARs and GluN2B subunit phosphorylation (Vedder et al., 2013), is completely responsible for the heightened LTP magnitude (Smith and McMahon, 2006). Recently, we reported that this E2-induced increase in novel object acknowledgement (NOR) only occurs at time points when the GluN2B-containing NMDAR current and LTP are also increased (Vedder et al., 2013). Furthermore, pharmacological blockade of GluN2B-containing NMDARs in area CA1 via stereotaxically placed cannulas only prevents the E2-enhanced NOR in OVX rats, linking together heightened LTP magnitude (Smith and McMahon, 2006) with heightened NOR Compound 401 (Vedder et al., 2013). In addition to the input from CA3 pyramidal cells, CA1 pyramidal cells receive a direct cortical input from layer III of the entorhinal cortex (temporoammonic pathway, TA) which synapses onto CA1 distal dendrites in stratum lacunosum-moleculare (SLM). A role for the TA pathway in modifying spatial learning and novelty detection have been established by numerous lesion (Ferbinteanu et al., 1999; Kirkby and Higgins, 1998; Remondes and Schuman, 2004; Vnek et al., 1995) and pharmacological studies (Hunsaker et al., 2007; Vago et al., 2007; Vago and Kesner, 2008). Compound 401 Experimental data and computer modeling suggest that strong input to CA1 cells from your TA pathway is critical in memory encoding, while strong input from CA3 pyramidal cells is critical during memory retrieval (Manns et al., 2007). These data show that activity at both pathways is required for normal hippocampus-dependent learning and memory. Given its position in the circuit and the particular timing of activity, the TA pathway can dictate whether SC-CA1 synapses will drive CA1 pyramidal cells to spike. Additionally, TA-CA1 synapses undergo NMDAR-dependent LTP and LTD (Aksoy-Aksel and Manahan-Vaughan, 2015;.