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Alejandro Lomniczi

Publications and source records attributed to Alejandro Lomniczi.

12 recordsLinked to original sources
PubMed2006

Quantitative proteomics identifies a change in glial glutamate metabolism at the time of female puberty.

Mammalian puberty requires activation of luteinizing hormone-releasing hormone (LHRH) neurons. In turn, these neurons are controlled by transsynaptic and glia-to-neuron communication pathways, which employ diverse cellular proteins for proper function. We have now used a high throughput relative quantitative proteomics technique to identify such proteins. We selected the method of two-dimensional liquid chromatography tandem mass spectrometry (2DLC-MS/MS) and cleavable isotope-coded affinity tags (cICAT), to both identify and quantify individual proteins within a complex protein mixture. The proteins used derived from the hypothalamus of juvenile (25-day-old) and peripubertal (first proestrus, LP) female rats, and their identity was established by analyzing their mass spectra via database searching. Five proteins involved in glutamate metabolism were detected and two of them appeared to be differentially expressed. They were selected for further analysis, because of their importance in controlling glutamate synthesis and degradation, and their preferential expression in astroglial cells. One, glutamate dehydrogenase (GDH) catalyzes glutamate synthesis; its hypothalamic content detected by 2DLC-MS/MS increases at first proestrus. The other, glutamine synthetase (GS), catalyzes the metabolism of glutamate to glutamine; its content decreases in proestrus. Western blot analysis verified these results. Because these changes suggested an increased glutamate production at puberty, we measured glutamate release from hypothalamic fragments from juvenile 29-day old rats, and from rats treated with PMSG to induce a premature proestrus surge of luteinizing hormone (LH). To determine the net output of glutamate in the absence of re-uptake we used the excitatory amino acid transporter (EAAT) inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC). PDC elicited significantly more glutamate- and LHRH-release from the proestrus hypothalamus. Thus, an increase excitatory drive to the LHRH neuronal network provided by glutamatergic inputs of glial origin, is an event contributing to the pubertal activation of LHRH secretion.

Age Factors↗
PubMed2006

Decrease in salivary secretion by radiation mediated by nitric oxide and prostaglandins.

OBJECTIVE: In the present work, we evaluated the effect of exposing the submandibular glands (SMG) to radiation, studying different functional parameters such as salivary secretion, nitric oxide (NO) production, reactive oxygen species formation, prostaglandin (PGE) content and apoptosis. METHODS: We irradiated rats in the head and neck region with a single dose of gamma-ray radiation of 15 Gy. Two hours after radiation, we measured norepinephrine-induced salivary secretion. After that, the SMG were dissected, and in this tissue, we measured the activity of NO synthase (NOS), the PGE content, the amount of reactive oxygen species, apoptotic cells and mitochondrial inducible NOS (iNOS) expression. RESULTS: We found that radiation decreased salivary secretion when 10 and 30 microg/kg of norepinephrine was administered via the right femoral vein. We observed that iNOS activity was reduced and PGE content increased after radiation in SMG, indicating that NO and PGEs may participate in salivary secretion. The expression of mitochondrial NOS was increased after radiation leading to the formation of large amounts of NO that acts as a proapoptotic signal. In fact, we observed an augmentation in apoptotic cells. In this study, we also observed an increase in lipid peroxidation induced by radiation that may contribute to tissue damage. CONCLUSIONS: Our results indicate that radiation induced a decrease in salivary secretion and SMG iNOS activity, meanwhile the PGE content, the lipid peroxidation and apoptosis increased in the tissue. These modifications decrease salivary secretion.

Animals↗
PubMed2006

Hypothalamic tumor necrosis factor-alpha converting enzyme mediates excitatory amino acid-dependent neuron-to-glia signaling in the neuroendocrine brain.

Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor alpha (TGFalpha) results in production of prostaglandin E2, which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-to-neuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs). Because the metalloproteinase tumor necrosis factor alpha converting enzyme (TACE) releases TGFalpha from its transmembrane precursor before TGFalpha can bind to erbB1 receptors, we sought to determine whether TACE is required for excitatory amino acids to activate the TGFalpha-erbB1 signaling module in hypothalamic astrocytes, and thus facilitate the advent of puberty. Coactivation of astrocytic AMPARs and mGluRs caused extracellular Ca2+ influx, a Ca2+/protein kinase C-dependent increase in TACE-like activity, and enhanced release of TGFalpha. Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence (ME), and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. ME explants respond to stimulation of AMPARs and mGluRs with LHRH release, and this response is prevented by blocking TACE activity. In vivo inhibition of TACE activity targeted to the ME delayed the age at first ovulation, indicating that ME-specific changes in TACE activity are required for the normal timing of puberty. These results suggest that TACE is a component of the neuron-to-glia signaling process used by glutamatergic neurons to control female sexual development.

ADAM Proteins↗
PubMed2006

Neuroendocrine mechanisms controlling female puberty: new approaches, new concepts.

Sexual development and mature reproductive function are controlled by a handful of neurones that, located in the basal forebrain, produce the decapeptide luteinizing hormone releasing hormone (LHRH). LHRH is released into the portal system that connects the hypothalamus to the pituitary gland and act on the latter to stimulate the synthesis and release of gonadotrophin hormones. The pubertal activation of LHRH release requires coordinated changes in excitatory and inhibitory inputs to LHRH-secreting neurones. These inputs are provided by both transsynaptic and glia-to-neurone communication pathways. Using cellular and molecular approaches, in combination with transgenic animal models and high-throughput procedures for gene discovery, we are gaining new insight into the basic mechanisms underlying this dual control of LHRH secretion and, hence, the initiation of mammalian puberty. Our results suggest that the initiation of puberty requires reciprocal neurone-glia communication involving excitatory amino acids and growth factors, and the coordinated actions of a group of transcriptional regulators that appear to represent a higher level of control governing the pubertal process.

Animals↗
PubMed2005

Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach?

The initiation of mammalian puberty requires an increase in pulsatile release of GnRH from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication. As the neuronal and glial excitatory inputs to the GnRH neuronal network increase, the transsynaptic inhibitory tone decreases, leading to the pubertal activation of GnRH secretion. The excitatory neuronal systems most prevalently involved in this process use glutamate and the peptide kisspeptin for neurotransmission/neuromodulation, whereas the most important inhibitory inputs are provided by gamma-aminobutyric acid (GABA)ergic and opiatergic neurons. Glial cells, on the other hand, facilitate GnRH secretion via growth factor-dependent cell-cell signaling. Coordination of this regulatory neuronal-glial network may require a hierarchical arrangement. One level of coordination appears to be provided by a host of unrelated genes encoding proteins required for cell-cell communication. A second, but overlapping, level might be provided by a second tier of genes engaged in specific cell functions required for productive cell-cell interaction. A third and higher level of control involves the transcriptional regulation of these subordinate genes by a handful of upper echelon genes that, operating within the different neuronal and glial subsets required for the initiation of the pubertal process, sustain the functional integration of the network. The existence of functionally connected genes controlling the pubertal process is consistent with the concept that puberty is under genetic control and that the genetic underpinnings of both normal and deranged puberty are polygenic rather than specified by a single gene. The availability of improved high-throughput techniques and computational methods for global analysis of mRNAs and proteins will allow us to not only initiate the systematic identification of the different components of this neuroendocrine network but also to define their functional interactions.

Animals↗
PubMed2004

erbB-1 and erbB-4 receptors act in concert to facilitate female sexual development and mature reproductive function.

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2+/+ or double-mutant astrocytes failed to respond to TGF alpha with production of prostaglandin E2, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2+/+ or double-mutant astrocytes treated with TGF alpha failed to stimulate LHRH release from GT1-7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.

Animals↗
PubMed2003

Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain.

Hypothalamic astroglial erbB tyrosine kinase receptors are required for the timely initiation of mammalian puberty. Ligand-dependent activation of these receptors sets in motion a glia-to-neuron signaling pathway that prompts the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, from hypothalamic neuroendocrine neurons. The neuronal systems that may regulate this growth factor-mediated back signaling to neuroendocrine neurons have not been identified. Here we demonstrate that hypothalamic astrocytes contain metabotropic receptors of the metabotropic glutamate receptor 5 subtype and the AMPA receptor subunits glutamate receptor 2 (GluR2) and GluR3. As in excitatory synapses, these receptors are in physical association with their respective interacting/clustering proteins Homer and PICK1. In addition, they are associated with erbB-1 and erbB-4 receptors. Concomitant activation of astroglial metabotropic and AMPA receptors results in the recruitment of erbB tyrosine kinase receptors and their respective ligands to the glial cell membrane, transactivation of erbB receptors via a mechanism requiring metalloproteinase activity, and increased erbB receptor gene expression. By facilitating erbB-dependent signaling and promoting erbB receptor gene expression in astrocytes, a neuron-to-glia glutamatergic pathway may represent a basic cell-cell communication mechanism used by the neuroendocrine brain to coordinate the facilitatory transsynaptic and astroglial input to LHRH neurons during sexual development.

Animals↗
PubMed2003

Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes.

The initiation of mammalian puberty requires the activation of hypothalamic neurons secreting the neuropeptide luteinizing hormone-releasing hormone (LHRH). It is thought that this activation is caused by changes in trans-synaptic input to LHRH neurons. More recently, it has been postulated that the pubertal increase in LHRH secretion in female animals also requires neuron-glia signaling mediated by growth factors of the epidermal growth factor (EGF) family and their astrocytic erbB receptors. Although it appears clear that functional astrocytic erbB1 receptors are necessary for the timely advent of puberty, the physiological contribution that erbB4 receptors may make to this process has not been established. To address this issue, we generated transgenic mice expressing a dominant-negative erbB4 receptor (DN-erbB4) under the control of the GFAP promoter, which targets transgene expression to astrocytes. DN-erbB4 expression is most abundant in hypothalamic astrocytes, where it blocks the ligand-dependent activation of glial erbB4 and erbB2 receptors, without affecting erbB1 (EGF) receptor signaling. Mice carrying the transgene exhibit delayed sexual maturation and a diminished reproductive capacity in early adulthood. These abnormalities are related to a deficiency in pituitary gonadotropin hormone secretion, caused by impaired release of LHRH, the hypothalamic neuropeptide that controls sexual development. In turn, the reduction in LHRH release is caused by the inability of hypothalamic astrocytes to respond to neuregulin (NRG) with production of prostaglandin E(2), which in wild-type animals mediates the stimulatory effect of astroglial erbB receptor activation on neuronal LHRH release. Thus, neuron-astroglia communication via NRG-erbB4/2 receptor signaling appears to be essential for the timely unfolding of the developmental program by which the brain controls mammalian sexual maturation.

Animals↗
PubMed2003

Glia-to-neuron signaling and the neuroendocrine control of female puberty.

The sine qua non event of puberty is an increase in pulsatile release of gonadotrophin hormone releasing hormone (GnRH). It is now clear that this increase and, therefore, the initiation of the pubertal process itself, require both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. While neurons that utilize excitatory and inhibitory amino acids as transmitters represent major players in the transsynaptic control of puberty, glial cells utilize a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and, thus, promote sexual development. A coordinated increase in glutamatergic transmission accompanied by a decrease in inhibitory GABAergic tone appears to initiate the transsynaptic cascade of events leading to the pubertal increase in GnRH release. Glial cells facilitate GnRH secretion via cell-cell signaling loops mainly initiated by members of the EGF and TGF- families of trophic factors, and brought about by either these factors themselves or by chemical messengers released in response to growth factor stimulation. In turn, a neuron-to-glia communication pathway mediated by excitatory amino acids serves to coordinate the simultaneous activation of transsynaptic and glia-to-neuron communication required for the advent of sexual maturity. A different--and perhaps higher--level of control may involve the transcriptional regulation of subordinate genes that, by contributing to neuroendocrine maturation, are required for the initiation of the pubertal process.

Animals↗
PubMed2003

The neurobiology of female puberty.

In this review, studies are described indicating that the increase in pulsatile release of gonadotropin releasing hormone that signals the initiation of puberty requires both changes in transsynaptic communication and the activation of glia-to-neuron signaling pathways. The major players in the transsynaptic control of puberty are neurons that utilize excitatory and inhibitory amino acids as transmitters. Glial cells employ a combination of trophic factors and small cell-cell signaling molecules to regulate neuronal function and thus promote sexual development. A neuron-to-glia signaling pathway mediated by excitatory amino acids serves to coordinate the simultaneous activation of transsynaptic and glia-to-neuron communication required for the advent of sexual maturity.

Animals↗
PubMedDate not supplied

Effect of nutritional stress on the hypothalamo-pituitary-gonadal axis in the growing male rat.

BACKGROUND/OBJECTIVE: Nutritional dwarfing (ND) consists of a decrease in weight and height gain and delayed onset of puberty. The aim of the present investigation was to study the modifications induced in male rats by the nutritional stress of a mere 20% reduction in food intake which, however, started immediately after weaning. MATERIALS AND METHODS: At weaning, male Wistar rats were divided into two groups: Control (C) and ND. C rats were fed ad libitum with a balanced rodent diet. ND received 80% of the diet consumed by C for 4 weeks (T4); then they were fed ad libitum for another 4 (T8) and 8 weeks (T12). The rats were studied at T0, T4, T8 and T12 for the effects of nutritional stress and refeeding on nutritional status, body composition, hypothalamic-pituitary-gonadal axis, and sperm morphology and concentration. RESULTS: ND body weight and length diminished vs. C (p < 0.001). ND body fat percentage decreased 40% (p < 0.001) without change in the percentage of body protein content. The hypothalamic content of LHRH did not change. However, FSH, LH and testosterone serum levels had significantly decreased (p < 0.001) at T4 in ND rats. A 48.4 % decrease in serum leptin in the ND group was observed at T4 (p < 0.05). The absolute testicular and seminal vesicle weight was significantly decreased by ND at T4 (p < 0.001). At T4 the percentage of anomalies of caudal spermatozoa increased in about 64% (p < 0.001) of ND vs. C rats, despite the unchanged sperm concentrations. All parameters normalized during refeeding. CONCLUSION: In this model, a decrease in leptin due to nutritional stress could be responsible, at least in part, for the inhibition of reproductive function. Refeeding normalized all parameters studied.

Animals↗