Elsevier

Brain Research

Volume 778, Issue 2, 19 December 1997, Pages 430-438
Brain Research

Interactive report
Estrogen facilitates induction of long term potentiation in the hippocampus of awake rats1

https://doi.org/10.1016/S0006-8993(97)01206-7Get rights and content

Abstract

In order to test the hypothesis that circulating levels of estrogen modulate synaptic plasticity in the hippocampus, we have studied the induction of long term potentiation (LTP) in awake rats. Ovariectomized animals, chronically implanted with a recording electrode in the cell body layer of CA1 and a stimulating electrode in stratum radiatum, were used to record evoked field potentials (population spike (PS) and summed EPSP) daily for at least 4 days before injection of sesame oil or 100 μg of estradiol benzoate per kg b.w. (E2). Basal levels of response to single square pulses (0.01 ms pulse width) delivered at 0.05 Hz through the stimulating electrode were recorded daily for 2 days after injection. To induce LTP a high-frequency `theta pattern' stimulation was administered. Basal recordings at low-frequency stimulation did not change after injection. After high-frequency stimulation all (7/7) E2 injected animals showed LTP whereas only 1/6 oil injected controls did so; the mean increase in amplitude of the PS and slope of the EPSP after high-frequency stimulation were significantly greater in E2 treated rats. Input/output curves did not change significantly after E2 administration. These results show that at low-frequency stimulation, transynaptic responses of pyramidal neurones in CA1 are not affected by changes in levels of circulating estrogen, while synaptic plasticity — which is at the basis of proposed hebbian associative memory — is facilitated by estrogen treatment.

Introduction

Levels of circulating estrogen influence sexual behavior and other forms of behavior that are not directly associated with reproduction, such as body temperature, running activity, food ingestion, aggression, sensory sensitivity, mood and performance in memory tests (for review see 42, 31). Although there has been considerable progress in the understanding of the cellular and systemic mechanisms responsible for these changes, many aspects of the neurobiology of steroid action remain unresolved. In this respect, the structural changes of neuronal assemblies responsible for instrumental control of specific responses have been the subject of considerable interest [35]. Previous work indicates that administration of estradiol to ovariectomized rats induces synaptic remodeling and growth in the ventromedial [7]and arcuate 29, 30hypothalamic nuclei. A series of reports from McEwen's laboratory have demonstrated that this phenomenon is produced by an increase in the number of dendritic spines [14], extending these observations to the hippocampus [16]and showing that this also occurs as a consequence of the normal waxing and waning of estradiol levels along the reproductive cycle of rats [54]. More recently, data from the same laboratory have demonstrated that in the CA1 of estradiol treated rats, pyramidal neurons harbor increased levels of NMDAR1 mRNA and protein [15], findings that explain the greater sensitivity of these neurons to NMDA, but not to AMPA, receptor-mediated synaptic input [55].

An inquiry into the functional consequences of these changes using intracellular recording showed that estradiol administration increased synaptic excitability and prolonged the EPSP in 20% of pyramidal neurons in CA1 [53], in coincidence with pioneering work by Terasawa and Timiras [46], who showed that estradiol treatment decreases hippocampal seizure threshold. At a greater level of complexity provided by the study of transynaptically evoked field potentials, Warren et al. [50]have found that induction of long term potentiation (LTP), which depends on synaptic plasticity, is maximal in female rats during the afternoon of proestrus. Accumulating evidence from a variety of experimental human 39, 22and animal 37, 27, 49, 12, 36, 23data indicate that estradiol may affect memory and learning processes. Since LTP is generally accepted as an electrophysiological model of memory, it should be useful to probe the functional variations generated by different levels of estradiol. This approach is particularly appealing because induction of LTP depends on the activation of NMDA receptors [5], which are increased by treatment with E2. Present experiments were designed to test the hypothesis that estradiol administration to ovariectomized females facilitates the induction of LTP.

Section snippets

Materials and methods

Adult (2–3 months old) Wistar derived female albino rats from our own colony, weighing 250–300 g, were ovariectomized (OVX) under ether anesthesia and maintained in a room with a reversed light-dark cycle (lights on from 21:00 to 09:00 h). At least 2 weeks later the animals were anesthetized with chloral hydrate (100 mg/ kg) and placed in a stereotaxic frame with the incisor bar set 3.3 mm below the plane of the interaural line, after Paxinos and Watson [38]. The electrodes consisted of two

Results

As previously described [3]a single pulse at the Schaffer collaterals evoked a positive going field EPSP in CA1. At higher stimulation intensity (defined as just above threshold), starting from the rising phase of the summed EPSP (Fig. 1), there appeared a single negative-going PS generated by synchronous firing of CA1 pyramidal neurons.

There was no effect of E2 treatment on the amplitude of the evoked PS (Fig. 2, A) through the recording period, up to 48 h after injection (E2 versus Oil; df3,

Discussion

Treatment of OVX rats with E2 facilitated the induction of LTP. As our results show, a stimulus paradigm that was subthreshold in OVX animals effectively induced LTP in E2-treated animals. Due to the fact that this finding was obtained in unanesthetized animals deprived of internal gonadal secretions, this effect can be directly ascribed to E2 and is in line with the well-documented excitatory, threshold-lowering capacity of estrogen [46]demonstrated in various experimental paradigms (see [21]

Acknowledgements

This work was made possible by grants from Consejo Nacional de Investigaciones Cientı́ficas y Técnicas of Argentina (CONICET) and Consejo de Investigaciones Cientı́ficas y Tecnológicas de Córdoba (CONICOR). D.A.C.M. was recipient of the Agustin Caeiro Fellowship from Fundación Interior Argentina (FUNINAR) and a Research Fellowship from CONICET. Comments and criticisms by Dr. S. Warren on a preliminary version of this report are gratefully acknowledged.

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