Biomedical subjects

J Epelbaum

Publications and source records attributed to J Epelbaum.

At least 19 recordsLinked to original sources

PubMed2006

Age-related alterations of GABAergic input to CA1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus.

The aim of this study was to determine whether age-associated alterations in the GABAergic input to pyramidal neurons in the hippocampus are due to a dysfunction of GABAergic interneurons, and/or a decrease in their cholinergic control via nicotinic receptors (nAChRs). Electrophysiological recordings were obtained from pyramidal cells in the CA1 area of hippocampal slices from young (3-4 months old) and aged (25-30 months old) Sprague-Dawley rats. Synaptic GABA(A) receptor-mediated inhibitory postsynaptic currents and inhibitory postsynaptic potentials induced by stimulation of the stratum oriens were significantly smaller in aged rats. The frequency (but not amplitude) of spontaneous and miniature GABA inhibitory postsynaptic currents (IPSCs) was reduced in aged rats, suggesting a presynaptic alteration. Tetanic stimulation of cholinergic afferents to release endogenous acetylcholine, or an exogenous application of the nAChR agonist cytisine, increased the frequency of spontaneous IPSCs in young rats; however these effects were not evident in aged rats, indicating that the nicotinic control of GABA release is lowered during aging. None of these age-related alterations were reversed by a chronic treatment with donepezil, a cholinesterase inhibitor. Immunofluorescent labeling of GABA interneurons with somatostatin (SOM), parvalbumin (PV) or calbindin (CB), together with the vesicular acetylcholine transporter VAChT, revealed a selective loss of subpopulations of SOM and CB positive interneurons. This loss was associated with a general decrease in density of the cholinergic network in aged rats. Thus, the lower GABAergic inhibition observed in the aged rat hippocampus is due to a selective loss/dysfunction of subpopulations of GABAergic interneurons, associated with a widespread cholinergic deficit.

Age Factors↗

PubMed2006

Pituitary cocaine- and amphetamine-regulated transcript expression depends on the strain, sex and oestrous cycle in the rat.

Cocaine- and amphetamine-regulated transcript (CART) mRNA and peptides are abundant in the adenohypophysis, but their role in pituitary function has not yet been elucidated. CART peptides were recently shown to colocalise with luteinising hormone (LH) or prolactin in rat anterior pituitary, and contradictory results concerning the peptide effects on pituitary hormonal secretions were obtained in vitro from pituitary cell cultures. Thus, we reinvestigated the expression of CART mRNA within the pituitary. Immunohistochemistry for pituitary hormones was performed on sections from adult male Wistar rats followed by in situ hybridisation using CART mRNA antisense 35S-labelled probes. The most represented CART-expressing cells were lactotrophs (42 +/- 1% of CART cells) and gonadotrophs (32 +/- 3%), followed by thyrotrophs (10 +/- 2%), corticotrophs (7 +/- 2%) and somatotrophs (6 +/- 1%). In the pars tuberalis, CART mRNA was easily detectable in gonadotrophs and lactotrophs and, to a lesser extent, in corticotrophs and thyrotrophs. CART peptide was quickly and potently released from perifused pituitary by depolarisation (K+ 30 mM for 15 min; 465 +/- 37% over basal release, n = 5). Gonadotrophin-releasing hormone and thyrotrophin-releasing hormone (0.1 microM) were also active to a lesser extent (138 +/- 11% and 71 +/- 17, n = 7, respectively). CART (0.1 microM) did not modify basal LH or prolactin release but selectively inhibited K+-induced LH release without affecting K+-induced prolactin secretion. Pituitary CART mRNA and content were sex dependent and varied during the oestrous cycle, being lower in dioestrous 2. Pituitary CART content also varied widely amongst rat strains being five to six-fold higher in Wistar and Fischer rats compared to Brown Norway and Lou C rats. Ageing differentially affected pituitary CART mRNA and content, resulting in a marked decrease in Lou C and an increase in Wistar and Sprague-Dawley rats. Taken together, these results suggest that pituitary CART expression is dependent of the sex steroid environment and may be physiologically involved in LH secretion.

Aging↗

PubMed2006

Motherhood-induced memory improvement persists across lifespan in rats but is abolished by a gestational stress.

Motherhood modifies the biology and behavior of the female, a process which prepares the mother's cognitive systems that are needed for nurturance. It has recently been shown that motherhood enhances hippocampal-mediated spatial learning and synaptic plasticity. Deleterious and long-term effects of a stress experienced during gestation have been demonstrated on progeny. Surprisingly little is known about the effect of such stress on mothers. Here, we investigated the effect of gestational stress on the adaptive changes due to motherhood. Female rats were mated and stressed during the last week of gestation. Two weeks after weaning, they were submitted to behavioral tests or electrophysiological study. A group of females were then kept for 16 months after motherhood experience to study the long-term effect of gestational stress and motherhood on memory when they were 22 months old. We confirm that a single motherhood experience selectively increases hippocampal-mediated spatial memory during the entire lifespan of female rats and protects them from age-associated memory impairments. However, we demonstrate that a stressful experience during gestation totally abolishes the positive effects of motherhood both on spatial memory and on hippocampal synaptic plasticity (long-term potentiation). Environmental factors that induce biological vulnerability have negative effects even for fundamental biological behaviors.

Animals↗

PubMed2006

A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory.

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.

Aging↗

PubMed2005

Donepezil restores GH secretion in old rats without affecting the sleep/wake cycle.

A chronic treatment with a cholinesterase inhibitor, donepezil (0.085 mg/kg/h for 30 days) increases significantly the number and amplitude of growth hormone (GH) pulses in 3- and 24-month-old rats without modifying nadir GH values. This treatment does not reduce age-related alterations in sleep/wake cycle but it increases immobility-related high-voltage spindles (HVS) in old animals. These data suggest that cholinergic mechanisms involved in age-related alterations in GH and sleep regulation are different.

Acetylcholinesterase↗

PubMed2005

Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifying GH Pulse amplitude: evidence from antagonism of the GH secretagogue-R1a receptor.

Ghrelin was purified from rat stomach as an endogenous ligand for the GH secretagogue (GHS) receptor. As a GHS, ghrelin stimulates GH release, but it also has additional activities, including stimulation of appetite and weight gain. Plasma GH and ghrelin secretory patterns appear unrelated, whereas many studies have correlated ghrelin variations with food intake episodes. To evaluate the role of endogenous ghrelin, GH secretion and food intake were monitored in male rats infused sc (6 mug/h during 10 h) or intracerebroventricularly (5 microg/h during 48 h) with BIM-28163, a full competitive antagonist of the GHS-R1a receptor. Subcutaneous BIM-28163 infusion significantly decreased GH area under the curve during a 6-h sampling period by 54% and peak amplitude by 46%. Twelve hours after the end of treatment these parameters returned to normal. Central treatment was similarly effective (-37 and -42% for area under the curve and -44 and -49% for peak amplitude on the first and second days of infusion, respectively). Neither peripheral nor central BIM-28163 injection modified GH peak number, GH nadir, or IGF-I levels. In this protocol, food intake is not strongly modified and water intake is unchanged. Subcutaneous infusion of BIM-28163 did not change plasma leptin and insulin levels evaluated at 1200 and 1600 h. On the contrary, central BIM-28163 infusion slightly increased leptin and significantly increased insulin concentrations. Thus, endogenous ghrelin, through GHS-R1a, acts as a strong endogenous amplifier of spontaneous GH peak amplitude. The mechanisms by which ghrelin modifies food intake remain to be defined and may involve a novel GHS receptor.

Animals↗

PubMed2005

[Biological aspects of longevity and ageing].

Despite very different life expectancies, a 2-year-old mouse, a 12-year-old dog, a 32-year-old chimpanzee or an 80-year-old man will share many common deficits such as a reduction in tissue elasticity, immunological responses, muscular strength, sensory perceptions, reflexes, as well as memory losses and increase of age-associated diseases (osteoporosis, osteoarthritis, type II diabetes, cardiovascular diseases, cataract and macular degeneration, neurodegenerative diseases, to name only a few...). With the increase of life expectancy in human species, ageing has become a major concern for the society, both at the human and financial level. The main challenge for biologists studying ageing is to understand how the multiple effects quoted above, so easily identifiable in various species, are nonetheless so coordinate among individuals of a given species. The acquisition of this fundamental knowledge will be essential to reach the ultimate goal of healthy ageing for human populations. At the present time, three types of recent developments on ageing research can be distinguished: 1) A consensus on evolutionist theory of ageing is developing. This theory is based on the fact that long-lived species usually arise from protected ecological niches. It implies that phenotypes which are expressed late in "aged survivors" are beyond natural selection. So, alleles underlying this late expression being adaptive or not ("good" or "bad"), contribute only slightly to the pool of genes of the following generation. 2) Study of laboratory models like the nematode C. elegans or fly D. melanogaster have enabled the observation that single-gene invalidation can increase lifespan. Interestingly, some of these changes seem to imply a common process through insulin/IGF-1 (insulin like growth factor-I) orthologue, energy metabolism and growth implicated hormones, as well as protection against free radicals. 3) In the mouse, several genes mutation increase lifespan and are associated with a decrease in growth hormone (GH) secretion as well as its main effector IGF-1. The study of such transgenic mutants, in parallel with the well-known effect of the caloric restriction on ageing, open several tracks which should allow determining common mechanisms which regulate the mammalian lifespan.

Aged↗

PubMed2004

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease.

Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.

Adult↗

PubMed2004

Plasma and hypothalamic peptide-hormone levels regulating somatotroph function and energy balance in fed and fasted states: a comparative study in four strains of rats.

Both growth hormone (GH)/insulin growth factor (IGF)-1 axis and energy balance have been implicated in longevity independently. The aim of the present study was to characterize the effect of a 72-h fasting period at 3 months of age in four different rat strains: (i) Wistar and (ii) Fischer 344 rats, which develop obesity with age, and (iii) Brown Norway and (iv) Lou C rats, which do not. Wistar rats ate more, were significantly bigger, and presented with higher plasma leptin and lower ghrelin levels and hypothalamic growth hormone-releasing hormone (GHRH) content than rats from the three other strains. Plasma insulin and IGF-1 levels were lower in Brown Norway and Lou C rats, and somatostatin content was lower in Brown Norway rats only. Glycaemia was lower in Lou C rats that displayed a lower relative food intake compared to Fischer and Wistar rats. Brown Norway rats showed a greater caloric efficiency than the three other strains. Concerning major hypothalamic neuropeptides implicated in feeding, similar amounts were detected in the four strains for neuropeptide Y, agouti-related peptide, galanin, melanin-concentrating hormone, alpha-melanocortin-stimulating hormone (alpha-MSH) and corticotropin-releasing hormone. Orexin A appeared to be slightly elevated in Fischer rats and cocaine amphetamine-regulated transcript (CART)(55-102) diminished in Brown Norway. At the mRNA level, orexin A, GHSR1, alpha-MSH and CART expression were higher in Wistar and Lou C rats. Principal component analysis confirmed the presence of two main factors in the ad libitum rat population; the first being associated with growth-related parameters and the second being associated with food intake regulation. Hypothalamic GHRH and somatostatin content were positively correlated with feeding-related neuropeptides such as alpha-MSH for GHRH, and orexin A and CART for both peptides. Plasma ghrelin levels were negatively correlated with leptin and IGF-1 levels. Finally, a 72-h fasting period affected minimally body weight, plasma IGF-1 and leptin levels in Lou C rats compared to the three other strains, and plasma insulin levels were less affected in Brown Norway rats. In conclusion, Wistar shorter life span is consistent with its already fatter phenotype at 3 months of age. In terms of IGF-1, glycaemia and leptin responses to fasting, the Lou strain, which presents with a low food intake/body weight and caloric efficiency, is the least affected. The link between food intake regulation, GH axis and ageing is further demonstrated by principal component analysis, where GHRH and somatostatin were found to be strongly associated with energy homeostasis parameters.

Aging↗

PubMed2003

Biological activity of somatostatin receptors in GC rat tumour somatotrophs: evidence with sst1-sst5 receptor-selective nonpeptidyl agonists.

The physiological actions of somatostatin-14 (SRIF: somatotrophin release inhibitory factor) receptor subtypes (sst(1)-sst(5)), which are endogenously expressed in growth cells (GC cells), have not yet been elucidated, although there is evidence that sst(2) receptors are negatively coupled to cytosolic free Ca(2+) concentration ([Ca(2+)](i)) and adenosine 3,5'-cyclic monophosphate (cAMP) accumulation. In addition, both sst(1) and sst(2) receptors are negatively coupled to growth hormone (GH) secretion in GC cells. Here we report on studies concerning the expression, the pharmacology and the functional role of native SRIF receptors in GC cells with the use of five nonpeptidyl agonists, highly selective for each of the SRIF receptors. Radioligand binding studies show that sst(2) and sst(5) receptors are present at different relative densities, while the presence of sst(3) and sst(4) receptors appears to be negligible. The absence of sst(1) receptor binding was unexpected in view of sst(1) receptor functional effects on GH secretion. This suggests very efficient receptor-effector coupling of a low-density population of sst(1) receptors. Functionally, only sst(2) receptors are coupled to the inhibition of [Ca(2+)](i) and cAMP accumulation and the selective activation of sst(5) receptors facilitates the stimulation of adenylyl cyclase activity through G(i/o) proteins. This effect was not observed when sst(2) and sst(5) receptors were simultaneously activated, suggesting that there is a functional interaction between sst(2) and sst(5) receptors. In addition, sst(1), sst(2) and sst(5) receptor activation inhibits GH release, further indicating that SRIF can modulate GH secretion in GC cells through mechanisms both dependent and independent on [Ca(2+)](i) and cAMP-dependent pathways. The present data suggest SRIF-mediated functional effects in GC cells to be very diverse and provides compelling arguments to propose that multiple native SRIF receptors expressed in the same cells are not simply redundant, but contribute to marked signalling diversity.

Amides↗

PubMed2003

The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease.

A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. By size exclusion chromatography, the cleavage of prosomatostatin to somatostatin-14 is almost totally abolished in the cortex of PC2 null mice, while the proportions of prosomatostatin and somatostatin-28 are increased. By immunohistochemistry, PC1 and PC2 were localized in many neuronal elements in human frontal and temporal cortex. The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2. No significant change in PC1 levels was observed in Alzheimer's disease. In contrast, a marked decrease in the ratio of the PC2 precursor to the total enzymatic pool was observed in the frontal cortex of Alzheimer patients. This decrease coincides with an increase in the binding protein 7B2. However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.

Adult↗

PubMed2003

Age-associated changes in hypothalamic and pituitary neuroendocrine gene expression in the rat.

A cDNA membrane array displaying 1183 probes was used to detect hypothalamic and pituitary changes in gene expression accompanying ageing and age-associated pituitary macroadenomas. Four groups of male Sprague-Dawley rats (3-, 15-, 24-month-old and 24-month-old with prolactinoma) were compared in two independent hybridizations. cDNA array data were confirmed and completed by comparative reverse transcriptase-polymerase chain reaction on selected genes. The expression of 454 and 116 mRNAs was detected in hypothalamus and pituitary, respectively. Growth hormone (GH) mRNA alone represented 85% of total gene expression in the gland of young rats, and other pituitary hormone transcripts 2.8%, while melanin-concentrating hormone (MCH) mRNA, the most expressed neuropeptide transcript involved in neuroendocrine regulation, accounted for only 0.8% of total hypothalamic transcripts. The proportion of genes modified in the hypothalamus and pituitary was rather modest: 1.5% and 5.2%, respectively, for ageing per se, and 1.1% and 5.2% for age-associated macroprolactinomas. Among pituitary specific RNAs, GH mRNA expression was notably decreased with age. At the hypothalamic level, expression of genes directly involved in GH regulation, such as somatostatin and growth hormone-releasing hormone, was not altered, while neuropeptide transcripts involved in feeding behaviour [orexin/hypocretin, MCH, pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART)] were significantly altered. In addition, a few ubiquitous transcripts (hnRNP-K, PFKm, CCND 2, calponin and set) were differently affected in both tissues. Modifications in hypothalamic orexigenic (orexin, MCH) and anorexigenic (POMC, CART) gene expression are in keeping with an age-associated decrease in energy consumption but a higher one in the presence of macroprolactinomas.

Aging↗

PubMed2003

Somatostatin receptors 2 and 5 are the major somatostatin receptors in insulinomas: an in vivo and in vitro study.

Somatostatin (SRIF) receptors (sst) are present on normal pancreatic endocrine beta-cells. However, the use of SRIF analogs in the scintigraphic imaging of insulinomas and in the medical management of these tumors seems to be restricted to a subgroup of patients. The aim of this study was to determine the prevalence of sst expression in vitro and characterize sst subtype binding in insulinomas and its correlation with in vivo sst receptor scintigraphy (SRS). In vitro studies were performed on 27 insulinomas from 25 patients: 22 with benign and three with malignant tumors. Semiquantitative RT-PCR of sst mRNAs was performed for 20 of these insulinomas. Sst2 and sst5 were expressed in 70%, sst1 in 50%, and sst3 and sst4 subtypes only in 15-20% of the tumors. (125)I-Tyr(0)DTrp(8)SRIF(14) binding was assessed by quantitative autoradiography in 18 insulinomas, and competition experiments were performed with SRIF(14) and L797-591, L779-976, L796-778, L803-087, L817-818, selective agonists of the five sst subtypes, and BIM23244, a selective agonist of sst2 and sst5. Significant specific binding was observed in 72% of the insulinomas. Displacement experiments with ligands of higher affinity for each of the sst receptors revealed significant binding with the sst2 and sst5 ligands in 72%, sst3 in 44%, sst1 in 44%, and sst4 in 28% of cases. All insulinomas displaying sst2 binding were also sst5 sensitive. However, the ratio of sst5/sst2 displacement was variable and only equal to that for SRIF(14) in experiments with the sst2/sst5 agonist BIM23244. SRS was performed 10 times in nine patients; it detected 60% of the tumors, including metastases of a malignant insulinoma. All the tumors detected by SRS displayed high levels of (125)I-Tyr(0)DTrp(8)SRIF(14) binding. The mechanisms underlying the loss of expression of sst2/sst5 in a third of insulinomas remains to be determined, but this loss of expression may be involved in beta-cell dysfunction.

Adult↗

PubMed2002

Somatostatin sst2 receptor knock-out mice: localisation of sst1-5 receptor mRNA and binding in mouse brain by semi-quantitative RT-PCR, in situ hybridisation histochemistry and receptor autoradiography.

The peptide hormone/neurotransmitter somatostatin (somatotropin release inhibiting factor; SRIF) and its receptors (sst(1)-sst(5)) appear to regulate many physiological functions in the CNS. Semi-quantitative analysis of the densities of mRNA expression for sst(1-5) receptors and SRIF receptor binding sites were established in sst(2) receptor knock-out (KO) mice. Patterns of sst(1-5) receptor mRNA expression were largely conserved for sst(1,3,4) and sst(5) selective oligonucleotide probes; whereas sst(2) signals were completely absent in KO mouse brain. Autoradiographic analysis demonstrated [(125)I]LTT SRIF(28), [(125)I]CGP 23996 (two radioligands known to label all five recombinant SRIF receptors) and [(125)I]Tyr(3)-octreotide (sst(2) and sst(5) receptor selective) binding in wild type (WT) mouse brain sections; yet no specific binding of [(125)I]Tyr(3)-octreotide in KO mice. In contrast, [(125)I]LTT SRIF(28) and [(125)I]CGP 23996 binding was still present in a number of brain areas in KO mice, although to a lesser degree than in those regions where [(125)I]Tyr(3)-octreotide binding was found, in WT animals. The present data suggest first, that both sst(2) receptor protein and mRNA were completely absent in the brain of these KO animals. Second, there was little evidence of compensatory regulation, at the mRNA level, of the other SRIF receptors as a consequence of the sst(2) KO. Third, the absence of any [(125)I]Tyr(3)-octreotide binding, in KO mice, suggests that this particular ligand is selective for the sst(2) receptor subtype (under the conditions utilised); or that sst(5) receptors are only marginally expressed in brain. Fourth, there were regions where the binding of [(125)I]LTT SRIF(28) and [(125)I]CGP 23996 were moderately affected by the sst(2) KO, suggesting that additional SRIF receptors may well contribute to the binding of the aforementioned radioligands. Finally, since the relative distribution of these two ligands were not entirely superimposable, it suggests that their respective selectivity profiles towards the different SRIF receptor subtypes in situ are not identical.

Animals↗

PubMed2002

Decrease in calbindin content significantly alters LTP but not NMDA receptor and calcium channel properties.

The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP) to the synaptic plasticity was investigated in hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice. We showed that long-term potentiation (LTP) induced by tetanic stimulation in CaBP-deficient mice was impaired. The fundamental biophysical properties of NMDA receptors and their number were not modified in CaBP-deficient mice. We also demonstrated that the physiological properties of calcium channels were identical between genotypes. An insufficient Ca(2+) entry through NMDA receptors or calcium channels, or a decrease in NMDA receptor density are unlikely to explain this impairment of LTP. Interestingly, we showed that the loss of LTP was not prevented by glycine but was restored in the presence of a low concentration of the NMDA receptor antagonist D-APV (5 microM) and of the calcium chelator BAPTA-AM (5 microM). Moreover, we observed a loss of LTP in the wild-type mice when the postsynaptic tetanic-induced [Ca(2+)](i) rise is excessively increased. Conversely, a weaker tetanus stimulation allowed LTP induction and maintenance in CaBP-deficient mice. These results suggest that a higher cytosol [Ca(2+)](i), due to the decrease of CaBP expression may impair LTP induction and maintenance mechanisms without affecting the mechanisms of calcium entry. Thus, CaBP plays a critical role in long term synaptic plasticity by limiting the elevation of calcium rise in the cytosol to some appropriate spatio-temporal pattern.

Animals↗

PubMed2002

Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice.

Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered. Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.

Animals↗

PubMed2002

Comparison of somatostatin receptor expression in human gliomas and medulloblastomas.

The expression of the five somatostatin receptor subtypes, sst1-5 was compared on tissue containing glial tumours (glioblastomas or oligodendrogliomas), medulloblastomas, and on normal human cortex. By semiquantitative reverse transcription coupled to polymerase chain reaction, the receptor expression profiles were high in cortex and in tissue containing oligodendrogliomas. It was moderate in medulloblastomas. Tissue containing glioblastomas displayed lower expression of somatostatin receptor subtypes, sst1 and sst3 being mostly expressed. By 125I-Tyr0DTrp8 somatostatin-14 or 125I-Leu8DTrp22 Tyr25 somatostatin-28 autoradiography combined with synaptophysin immunohistochemistry, it was possible to differentiate between isolated tumoral cell component infiltrating the cerebral parenchyma (cortex or white matter) and tumoral tissue (without residual parenchyma) in glioblastomas or oligodendrogliomas. Glial tumoral tissue per se presented few somatostatin receptors. By contrast, medulloblastoma tumoral cells exhibited numerous octreotide sensitive somatostatin receptors. sst2 immunocytochemistry demonstrated immunostaining of neuronal cells and neuropile; sst2 and sst3 immunostaining was identified on glioblastoma proliferating vessels endothelial cells and on medulloblastomas tumoral cells. Faint sst2 immunostaining among glial tumoral cells was due to microglia, while glioma cells did not significantly stain. In summary, medulloblastoma tumoral cells express sst2/sst3 receptors at a high level while glioma cells do not. In gliomas, sst expression is restricted to endothelial cells on proliferating vessels (displaying both sst2 and sst3 receptors), including parenchyma and reactive microglia (only sst2). The differential expression of sst2/sst3 receptors on gliomas and medulloblastomas has implications for the therapy of these tumours.

Adolescent↗

PubMed2002

Overexpression of the V3 vasopressin receptor in transgenic mice corticotropes leads to increased basal corticosterone.

The vasopressin V3 receptor (V3) is specifically expressed in pituitary corticotropes and mediates the stimulatory effect of vasopressin on adrenocorticotropic hormone (ACTH) release. The V3 gene is overexpressed in corticotrope pituitary tumours compared to normal pituitaries. We hypothesized that V3 overexpression might induce changes in corticotrope function and alter the regulation of the hypothalamic-pituitary-adrenal axis. Thus, we generated transgenic mice (POMV3) expressing the human V3 receptor in the pituitary under the control of rat pro-opiomelanocortin (POMC) promoter sequences. The transgene was efficiently transcribed and vasopressin binding was increased in both corticotropes and melanotropes. In-vitro ACTH release and inositol phosphate formation were unchanged in POMV3 pituitaries, but the responses to vasopressin were significatively increased. In vivo, basal circulating concentrations of ACTH in POMV3 mice were similar to those of controls but corticosterone concentrations were moderately increased. In addition, the levels of POMC mRNA in the transgenic pituitaries were comparable to those of control mice. Finally, POMV3 mice responded with a similar maximal increase of ACTH and corticosterone to a 20-min acute restraint stress. Together, these results show that hypophyseal V3 overexpression led to increased basal concentrations of corticosterone and suggest that the negative glucocorticoid feedback may be altered at the pituitary level.

Animals↗