Coupling of neuronal nitric oxide synthase to NMDA receptors via postsynaptic density-95 depends on estrogen and contributes to the central control of adult female reproduction
ABSTRACT Considerable research has been devoted to the understanding of how nitric oxide (NO) influences brain function. Few studies, however, have addressed how its production is physiologically regulated. Here, we report that protein-protein interactions between neuronal NO synthase (nNOS) and glutamate NMDA receptors via the scaffolding protein postsynaptic density-95 (PSD-95) in the hypothalamic preoptic region of adult female rats is sensitive to cyclic estrogen fluctuation. Coimmunoprecipitation experiments were used to assess the physical association between nNOS and NMDA receptor NR2B subunit in the preoptic region of the hypothalamus. We found that nNOS strongly interacts with NR2B at the onset of the preovulatory surge at proestrus (when estrogen levels are highest) compared with basal-stage diestrous rats. Consistently, estrogen treatment of gonadectomized female rats also increases nNOS/NR2B complex formation. Moreover, endogenous fluctuations in estrogen levels during the estrous cycle coincide with changes in the physical association of nNOS to PSD-95 and the magnitude of NO release in the preoptic region. Finally, temporary and local in vivo suppression of PSD-95 synthesis by using antisense oligodeoxynucleotides leads to inhibition of nNOS activity in the preoptic region and disrupted estrous cyclicity, a process requiring coordinated activation of neurons containing gonadotropin-releasing hormone (the neuropeptide controlling reproductive function). In conclusion, our findings identify a novel steroid-mediated molecular mechanism that enables the adult mammalian brain to control NO release under physiological conditions.
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ABSTRACT: Nitric oxide (NO) is a gaseous neurotransmitter that plays an important role in the regulation of sexual behavior in rodents. NO is produced, within the central nervous system, by the enzyme neural NO synthase (nNOS) whose expression is influenced by gonadal hormones. In previous studies, we demonstrated that part of the nitrergic hypothalamic and limbic system is influenced, in physiological conditions, by the hormonal fluctuations during the estrous cycle, but we were unable to distinguish among the role played by progesterone (P) or estradiol (E(2)) in inducing these changes. In the present study, we investigated the effects of E(2) and P (alone or together) on the nitrergic system of gonadectomized female mice, following a timing of administration that emulates the different phases of estrous cycle. In parallel, we tested the influence of the two hormones on sexual behavior, confirming that P works in synergistic fashion with E(2) to facilitate female receptivity. The quantitative analysis of nNOS-ir system demonstrated a statistically significant variation in the number of positive cells only in those part of the limbic-hypothalamic nitrergic system that are affected in cycling females, i.e. the bed nucleus of the stria terminalis, the arcuate nucleus and the medial preoptic area, with the highest number of positive neurons observed in E(2)+P group. The variable effects of E(2) and P may depend on the different distribution of their receptors within the analyzed nuclei, but the relationships among variations of estrogen and progesterone levels and in vivo modulation of nNOS expression remain unknown and needed further investigations.Brain research 08/2011; 1404:1-9. DOI:10.1016/j.brainres.2011.06.017 · 2.83 Impact Factor
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ABSTRACT: Synaptic plasticity mechanisms are usually discussed in terms of changes in synaptic strength. The capacity of excitatory synapses to rapidly modify the membrane expression of glutamate receptors in an activity-dependent manner plays a critical role in learning and memory processes by re-distributing activity within neuronal networks. Recent work has however also shown that functional plasticity properties are associated with a rewiring of synaptic connections and a selective stabilization of activated synapses. These structural aspects of plasticity have the potential to continuously modify the organization of synaptic networks and thereby introduce specificity in the wiring diagram of cortical circuits. Recent work has started to unravel some of the molecular mechanisms that underlie these properties of structural plasticity, highlighting an important role of signaling pathways that are also major candidates for contributing to developmental psychiatric disorders. We review here some of these recent advances and discuss the hypothesis that alterations of structural plasticity could represent a common mechanism contributing to the cognitive and functional defects observed in diseases such as intellectual disability, autism spectrum disorders and schizophrenia.Frontiers in Neuroanatomy 11/2014; 8:123. DOI:10.3389/fnana.2014.00123 · 4.18 Impact Factor
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ABSTRACT: Bisphenol A (BPA) is a well-known plastic-derived pollutant that can bind to oestrogen receptors and is considered an endocrine-disrupting chemical. Its impact on different behaviours in rodents has been largely investigated, however, only a few data are available on its effects upon neural circuits. In the present study, we investigated the long-term effects of early exposure of mice of both sexes to BPA on the nitrinergic system, one of the neural systems involved in the control of sexual behaviour and under the control of gonadal hormones. Mice of both sexes were exposed for eight prenatal and eight postnatal days to BPA that was administered to the mothers. The maternally-exposed mice were sacrificed at the age of 2 months and their brains were sectioned and immunohistochemically treated for the detection of neuronal nitric oxide synthase (nNOS). Significant effects of BPA exposure were detected for the number of immunoreactive cells in the medial preoptic nucleus and in the ventromedial subdivision of the bed nucleus of the stria terminalis, in a sex-oriented and dose-dependent way. These results indicate that BPA has a powerful effect on specific portions of the nNOS-immunoreactive system belonging to the accessory olfactory system that are particularly important for the control of sexual behaviour. In addition, they confirm that perinatal exposure to endocrine-disrupting chemicals, in particular to BPA, may have a high impact on the organisation of specific neural pathways that can later affect complex behaviours and functions.Journal of Neuroendocrinology 09/2010; 22(9):1004-12. DOI:10.1111/j.1365-2826.2010.02043.x · 3.51 Impact Factor