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Fig. 1. Camera lucida drawings of apical dendrites of CA1 pyramidal neurons from ovariectomized rats either untreated (A) or treated (B) with estradiol and progesterone to induce spines. Scale bar = 10 µm. [Reproduced with permission from ref. 29 (Copyright 1990, Society for Neuroscience)].

(20), the involvement of AMPA receptors in response to ovarian steroid manipulations is not known. It remains to be determined whether the E-induced synapses are so-called “silent” synapses with only NMDA receptors (21) or ones that contain AMPA receptors as well. In contrast to the efficacy of NMDA receptor inhibition for synapse formation (see below), blockade of AMPA receptors with the antagonist NBQX during E treatment failed to block synaptogenesis (22).

Besides increasing NMDA currents, reducing seizure thresh-olds, and enhancing long-term potentiation in hippocampus, E treatment exerts effects on hippocampal-dependent learning and memory. Three types of effects have been reported. First, in the natural estrous cycle of the rat, a recent study has used a delayed matching-to-place task in female rats to show a close parallel between the temporal conditions by which E improves memory and the conditions for E to induce new excitatory synaptic connections in the hippocampus (9). Second, E treatment of ovariectomized rats has been reported to improve acquisition on a radial maze task as well as in a reinforced T-maze alternation task (23, 24). Third, sustained E treatment is reported to improve performance in a working memory task (25), as well as in the radial arm maze (24, 26). The effects of E replacement in rats are reminiscent of the effects of E treatment in women whose E levels have been suppressed by a gonadotrophin-releasing hormone agonist used to shrink the size of fibroids before surgery (10, 27).

Excitatory Synapse Formation in the Hippocampus

E treatment increases dendritic spine density on CA1 pyramidal neurons (Figs. 1 and 2). As observed by electron microscopy, E also induces new synapses on spines and not on dendritic shafts of CA1 neurons (28). There were no E effects on dendritic length or branching (3, 28, 29). Progesterone (P) treatment acutely enhances spine formation (Fig. 1). But, over a 12- to 24-h period, P caused the down-regulation of E-induced synapses (29, 30), as will be discussed further below.

Estrogens do not act alone, and, in fact, ongoing excitatory neurotransmission is required for synapse induction, as shown by the finding that antagonists of NMDA receptors block

Fig. 2. Number of dendritic spines per 10 µm obtained from the apical portion of the CA1 pyramidal cell dendritic tree. Values are the mean ± SEM for estrogen and estrogen plus 5-h progesterone treatment. E induces increased spine density, an effect that is enhanced by 5-h progesterone. **, Different from other groups, P< 0.01; *, different from E+P group, P< 0.05. [Reproduced with permission from ref. 29 (Copyright 1990, Society for Neuroscience)].

E-induced synaptogenesis on dendritic spines in ovariectomized female rats (ref. 22 and Fig. 3). Because E treatment increases the density of NMDA receptors in the CA1 region of the hippocampus (17, 31), the activation of NMDA receptors by glutamate may lead the way in causing new excitatory synapses to develop.

Spines are occupied by asymmetric, excitatory synapses and are sites of Ca2+ ion accumulation and contain NMDA receptors (32). NMDA receptors are expressed in large amounts in CA1 pyramidal neurons and can be imaged by conventional immunocytochemistry as well as by confocal imaging, in which individual dendrites and spines can be studied for colocalization with other markers (3335). Confocal microscopic imaging showed that E treatment up-regulates immunoreactivity for the largest NMDA receptor subunit, NR1, on dendrites and cell bodies of CA1 pyramidal neurons, whereas NR1 mRNA levels did not change after E treatment that induces new synapses (35), suggesting the possibility that NR1 expression is regulated posttranscriptionally by E (Fig. 4).

Nuclear Estrogen Receptors in the Hippocampus

Adult CA1 pyramidal cells appear to lack detectable nuclear ER as shown by tritium autoradiography (36) and light microscopic immunocytochemistry (4, 37), whereas they show low levels of ERa and -ß mRNA by in situ hybridization (38, 39). Autoradiographic mapping studies of [3H]estradiol uptake in hippocampus showed a sparse distribution of interneurons in the CA1 region, as well as other regions of Ammon’s horn that contain nuclear E binding sites (36). This observation was confirmed by immunocytochemistry for ERa in the guinea pig hippocampus (37) and subsequently in the rat hippocampus (ref. 4 and Fig. 5). These findings and those from cell culture studies described below led to a hypothesis regarding the role of interneurons as trans-synaptic regulators of synapse formation. Two other mechanisms will then be considered: (i) that E acts via a novel non-genomic mechanism; or (ii) that there are low levels of genomic ERs that are undetectable by conventional immunocytochemistry.

Cell Culture Model of Synapse Formation

Recent studies revealed that E induces spines on dendrites of dissociated hippocampal neurons in culture by a process that is blocked by an NMDA receptor antagonist and not by an AMPA/ kainate receptor blocker (40). In a subsequent study, E treatment was found to increase the phosphorylation of cAMP response

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