Role of the NMDA Receptors

Antagonists of NMDA receptors block estrogen-induced synaptogenesis on dendritic spines in ovariectomized female rats. Because estrogen treatment increases the density of NMDA receptors in the CA1 region of hippocampus, it is possible that activation of NMDA receptors by glutamate leads the way in causing new excitatory synapses to develop. Spines are occupied by asymmetric, excitatory synapses, and they are sites of Ca++ ion accumulation and thus ideal sites for NMDA receptors (118). 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 co-localization with other markers (119,120). NMDA receptor mRNA can also be measured by in situ hybridization, and four different forms show different regional patterns and developmental regulation (121). As previously noted, adult CA1 neurons lack detectable estrogen receptors as shown by autoradiography (38), immunocytochemistry (39), or in situ hybridization (122), leading to the conclusion that a trans-synaptic mechanism is involved from afferent projections and interneurons or that estradiol acts via a novel nongenomic mechanism, or that there are low and undetectable levels of genomic estrogen receptors. Although there is no basis at present to infer a nongenomic action of estradiol, the trans-synaptic notion is more credible and attractive, because both entorhinal cortex cells and hippocampal interneu-rons have estrogen receptors and project to the CA1 neurons and provide an anatomical pathway for the trans-synaptic estrogen induction of synapses. It should also be noted that the serotonergic system may play a role (see earlier).

NMDA receptors are implicated in other morphogenetic processes in the adult brain, such as suppressing neurogenesis in the dentate gyrus (46), and they are also involved in the developing nervous system as facilitators of neuronal migration (123,124). However, there is a noteworthy paradox, in that NMDA receptors are implicated during visual system development in the reduction of synaptic contact in the developing retinal axon arbors (125) and NMDA receptor blockade results in rapid acquisition of dendritic spines by visual thalamic neurons (40). It appears likely that hippocampus and visual-system neurons respond in opposite ways to NMDA receptors, because a recent report on embryonic hippocampal neurons in culture indicates that NMDA receptor blockade prevents estrogen-induced synaptogenesis induced by albeit, very high (^mol) levels of estradiol (126).

One problem with the dissociated cell-culture system for studies of mechanism, as opposed to an anatomically-organized hippocampus, is that cells in culture are difficult to characterize with respect to their neurochemical specialization and their synaptic connections with each other. Moreover, they are more of a model for developmental events, rather than regions- and cell-specific synaptogenesis in the adult hippocampus. Studies on hippocampal slices prepared from postnatal brains may be an useful way of studying the synaptogenesis phenomenon, because slices of the 14-d-old ferret thalamus have been used to study the opposite effect to that in hippocampus, namely a rapid increases in spine density after NMDA receptor blockade, and viable hippoc-ampal slice preparations from 25-d-old rat brains have been described (127,128). A model of synaptogenesis in the hippocampus is presented in Fig. 1, emphasizing the role of NMDA receptors and the possible role of afferents from the entorhinal cortex and 5HT input, as well as the possible role of the interneurons in which the estrogen receptors have been found.

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