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The Journal of Neuroscience, June 6, 2007, 27(23):6103-6114; doi:10.1523/JNEUROSCI.5595-06.2007

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Development/Plasticity/Repair
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

Xavier d'Anglemont de Tassigny,^1,2 Céline Campagne,^1,2 Bénédicte Dehouck,^1,2 Danièle Leroy,^1,2 Gay R. Holstein,³ Jean-Claude Beauvillain,^1,2 Valérie Buée-Scherrer,^1,2 and Vincent Prevot^1,2

¹Inserm, Jean-Pierre Aubert Research Centre, U837, Development and Plasticity of the Postnatal Brain, 59045 Lille cedex, France, ²University of Lille 2, School of Medicine, Institut de Médecine Prédictive et de Recherche Thérapeutique, 59046 Lille cedex, France, and ³Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029

Correspondence should be addressed to Dr. Vincent Prevot, Inserm U837, Bâtiment Biserte, Place de Verdun, 59045 Lille Cedex, France. Email: prevot{at}lille.inserm.fr

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.

Key words: neuronal nitric oxide synthase; glutamate; sex steroids; estrous cycle; LHRH; hypothalamus

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Received Nov. 29, 2005; revised April 19, 2007; accepted April 19, 2007.

Correspondence should be addressed to Dr. Vincent Prevot, Inserm U837, Bâtiment Biserte, Place de Verdun, 59045 Lille Cedex, France. Email: prevot{at}lille.inserm.fr

This article has been cited by other articles:

				J. Clasadonte, P. Poulain, J.-C. Beauvillain, and V. Prevot Activation of Neuronal Nitric Oxide Release Inhibits Spontaneous Firing in Adult Gonadotropin-Releasing Hormone Neurons: A Possible Local Synchronizing Signal Endocrinology, February 1, 2008; 149(2): 587 - 596. [Abstract] [Full Text] [PDF]

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