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.
- SourceAvailable from: Sebastien G Bouret
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ABSTRACT: Exposure to Bisphenol-A (BPA), an endocrine disruptor used in plastics, occurs in the United States on a daily basis. Recent studies suggest exposure during development causes memory deficits later in life; however, the ramifications of exposure in adulthood are unclear. We examined the effects of acute BPA administration (40 μg/kg) on memory and synaptic plasticity in adult male rats. BPA significantly impaired both visual and spatial memory and decreased dendritic spine density on pyramidal cells in CA1 and the medial prefrontal cortex (mPFC). Additionally, BPA significantly decreased PSD-95, a synaptic marker, in the hippocampus and increased cytosolic pCREB, a transcription factor, in mPFC. Together, these findings show that a single dose of BPA, below the USEPA reference safe daily limit of 50 μg/kg/day, may block the formation of new memories by interfering with neural plasticity processes in the adult brain.Behavioral Neuroscience 02/2012; 126(1):175-85. · 2.63 Impact Factor
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ABSTRACT: The hypothalamic melanocortin system, which includes neurons that produce pro-opiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher postweaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependent accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity.Cell metabolism 02/2012; 15(2):247-55. · 17.35 Impact Factor