Estrogen-Induced Increase in the Magnitude of Long-Term Potentiation Occurs Only When the Ratio of NMDA Transmission to AMPA Transmission Is Increased

Abstract

Elevated levels of estradiol enhance learning in mammals, including humans, likely a result of hormone-induced heightened plasticity at CA3-CA1 synapses. The increase in long-term potentiation (LTP) magnitude is considered to be a consequence of the estradiol-induced increase in dendritic spine density and NMDA receptor (NMDAR)-mediated transmission; however, direct evidence linking these changes together is lacking. Alternatively, alterations in GABAergic inhibition or presynaptic release probability could contribute. Here, we show in time course studies using hippocampal slices from estradiol-treated ovariectomized rats that the LTP magnitude is increased only when spine density is increased simultaneously with an increase in NMDAR transmission relative to AMPA receptor (AMPAR) transmission, with no role for alterations in GABAergic inhibition or release probability. With time after hormone treatment, AMPAR transmission gradually increases during the maintained increase in spine density and NMDAR transmission. Eventually, the balance between NMDAR and AMPAR transmission is reestablished, and the LTP magnitude is no longer increased. Blocking genomic estrogen receptors prevents the heightened spine density, NMDAR transmission, and LTP magnitude, suggesting a tight mechanistic coupling between these morphological and functional changes. Thus, we propose that the hormone-induced increase in functional synapse density alone is not sufficient to support heightened plasticity. Rather, estradiol increases LTP via enhancing NMDAR transmission, likely through receptor insertion into newly formed or preexisting synapses. Later, when excitability in the circuit is at its highest and spine density remains elevated, the LTP magnitude is no longer increased, probably as a consequence of the delayed increase in AMPAR transmission that resets the balance between NMDAR and AMPAR transmission.

Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity

“…wrote the paper. density in hippocampal neurons could be blocked by NDMAR antagonism (11,16). The transient effects of E2 on spine density were also observed in cells not chronically treated with APV ( Fig.…”

Bisphenol A Impairs Synaptic Plasticity by Both Pre‐ and Postsynaptic Mechanisms

“…The “pathological plasticity” of synapse may provide the cellular basis of behavioral alterations. It has been found that 17β‐estradiol interaction with estrogen receptors has potential to heighten the magnitude of LTP at hippocampal CA3–CA1 synapses in rats 24. We speculate that BPA may exert inhibitory effects on the hippocampus‐related function in developmental rats by blocking estrogen receptors to disturb 17β‐estradiol effects in the normal physiological state.…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Finally, for both estrogen and BDNF, the effects that have been observed exhibit unique and characteristic response patterns, that are not shared by any other humoral agent. Thus, estrogen has striking effects that range from alterations in behavior [5][6][7][8][9][10][11][12][13], structure (spine morphology, density, and spine synapses; Table 2), and physiology (potentiation of glutamatergic inputs in area CA1; Table 2) including specific receptormediated actions, such as actions at the NMDA receptor (although not exclusively; [14]). BDNF is the one other molecule that has been shown to exert many, if not all, of these same specific effects (Table 2).…”

“…Thus, both estradiol and BDNF exert some of their actions in CA1 by phosphorylating either NR1 or NR2B, two subunits of the NMDA receptor [14,[47][48][49][50][51][52][53][54][55]. They also have both been shown to influence a specific Ca2+ -dependent potassium current in CA1 pyramidal cells [56][57][58].…”