Somatostatin: a putative neurotrophic factor with pleiotropic activity in the rat central nervous system.
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Biomedical subjects
B J Gonzalez
Publications and source records attributed to B J Gonzalez.
Ontogeny of somatostatin receptors in the rat somatosensory cortex.
The distribution and density of SRIF receptors (SRIF-R) were studied during development in the rat somatosensory cortex by in vitro autoradiography with monoiodinated [Tyr0-DTrp8]S14. In 16-day-old fetuses (E16), intense labeling was evident in the intermediate zone of the cortex while low concentrations of SRIF-R were detected in the marginal and ventricular zones. The highest density of SRIF-R was measured in the intermediate zone at E18. At this stage, labeling was also intense in the internal part of the developing cortical plate; in contrast, the concentration of binding sites associated with the marginal and ventricular zones remained relatively low. Profound modifications in the distribution of SRIF-R appeared at birth. In particular, a transient reduction of receptor density occurred in the cortical plate. During the first postnatal week, the density of receptors measured in the intermediate zone decreased gradually; conversely, high levels of SRIF-R were observed in the developing cortical layers (II to VI). At postpartum day 13 (P13), a stage which just precedes completion of cell migration in the parietal cortex, the most intensely labeled regions were layers V-VI and future layers II-III. From P13 to adulthood, the concentrations of SRIF-R decreased in all cortical layers (I to VI) and the pattern of distribution of receptors at P21 was similar to that observed in the adults.(ABSTRACT TRUNCATED AT 250 WORDS)
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Transient expression of somatostatin receptors in the rat visual system during development.
The ontogeny of somatostatin receptors in the rat visual system was studied by auto-radiography, using [125I-Tyr0,DTrp8]S14 as a radioligand. The binding sites showed high affinity for somatostatin and somatostatin analogues, and were regulated by GTP as early as day 16 of fetal life (E16), indicating that they represent functional somatostatin receptors. The density of somatostatin receptors was quantified by computerized image-analysis of film autoradiograms, and by grain counting on emulsion-coated slides. During fetal life, somatostatin receptors were observed in the retina, optic nerve, optic chiasma, optic tract, and lateral geniculate nucleus. The highest densities of somatostatin receptors were measured from E16 to E18 in the retina and primary optic pathways. During the first postnatal days, the density of somatostatin receptors decreased dramatically in the retina. In both the optic pathways and dorsal lateral geniculate nucleus, somatostatin receptors gradually disappeared, and the levels of somatostatin receptors were almost undetectable at postnatal day 21 (P21). Conversely, the density of somatostatin receptors remained stable in the ventral lateral geniculate nucleus during the early postnatal life (P0-P7). The timing of expression and the localization of somatostatin receptors in the developing visual system suggest that the immature ganglion cells are responsible for the expression of these evanescent somatostatin receptors. After eye opening, the distribution patterns of somatostatin receptors in the retina and the lateral geniculate nucleus were similar to those observed in adults. In particular, from P14 onwards, somatostatin receptors were concentrated in the inner plexiform layer and, to a lesser extent, in the ganglion cell and photoreceptor layers. In the ventral lateral geniculate nucleus, a heterogeneous distribution of somatostatin receptors was noted, the highest densities being found in the intergeniculate leaflet and the medial zone limiting the parvo-magnocellular interface. The distribution of somatostatin receptors in the retina and the ventral lateral geniculate nucleus after the second postnatal week, together with the presence of somatostatin-like immunoreactive elements in these structures, provide support for the involvement of somatostatin as a neurotransmitter or neuromodulator in the visual system of the adult rat. Conversely, the transient expression of somatostatin receptors observed before maturation and complete organization of the optic pathways suggests that somatostatin plays a trophic role during development of the visual system.
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Expression of somatostatin receptors is impaired in the cerebellum of developing Brattleboro rats.
Somatostatin (SRIF) receptors are expressed in the external granule cell layer of the rat cerebellum during early postnatal life. The aim of the present study was to investigate the distribution and biochemical characteristics of SRIF binding sites in the cerebellum of homozygous (vasopressin deficient) Brattleboro rats, which exhibit a selective impairment of their granule cell layer. This study has been conducted in 13-day-old rats by means of membrane-binding assay and autoradiography using [125I-Tyr0,DTrp8]S14 as a radioligand. In the cerebellum of homozygous Brattleboro rats, Scatchard plot analysis revealed the existence of a single class of SRIF receptors with similar Kd values as in Long-Evans or heterozygous Brattleboro rats (180-200 pM). Conversely, a marked reduction of the concentration of SRIF binding sites was observed in Brattleboro rats as compared to heterozygous or Long-Evans rats. In homozygous Brattleboro rats, autoradiographic studies revealed that the concentration of SRIF receptors was reduced in all lobules of the cerebellum as compared to Long-Evans. In addition, the magnitude of the decrease of receptor concentration was greater than the loss of granule cells observed in the homozygous Brattleboro rat. These results indicate that the expression of SRIF receptors by immature granule cells of the cerebellum is markedly reduced in Brattleboro rats. Whether the impairment of SRIF receptors in diabetes insipidus rats can directly be ascribed to vasopressin deficiency remains to be determined.
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Pharmacological characterization of somatostatin receptors in the rat cerebellum during development.
Somatostatin (SRIF) receptors (SRIF-Rs) are transiently expressed in a germinative lamina of the rat cerebellum, the external granule cell layer. The appearance of SRIF-Rs coincides with the expression of SRIF-like immunoreactivity in the cerebellum. However, the cellular location of SRIF-Rs does not overlap with the distribution of SRIF-like immunoreactivity, with the latter being restricted to ascending fibers arising from the brainstem, to perikarya within the white matter, and to some Purkinje cells. The characterization of SRIF-Rs in the immature (13-day-old) rat cerebellum was conducted by means of binding experiments in membrane-enriched preparations and autoradiography, using two radioligands, [125I-Tyr0,D-Trp8]SRIF-14 [( 125I-Tyr0,D-Trp8]S14) and 125I-SMS 204-090. The pharmacological profile of cerebellar SRIF-Rs was compared with that of adult cortical SRIF-Rs. Saturation studies performed in 13-day-old rat cerebellum showed that the KD values for [125I-Tyr0,D-Trp8]S14 and 125I-SMS 204-090 binding were 0.35 +/- 0.04 and 0.39 +/- 0.01 nM, respectively. The corresponding Bmax values were 52.7 +/- 4.8 and 49.9 +/- 5.3 fmol/mg of protein, a result indicating that radioligands with high specific radioactivity (2,000 Ci/mmol) bind to a single class of high-affinity sites (SS1). Competition studies showed that different D-Trp-substituted analogs displaced [125I-Tyr0,D-Trp8]S14 binding with Hill coefficients less than 1, a finding indicating the existence of different subtypes of binding sites. When [Tyr0,D-Trp8]S14 was used as a competitor, two sites were resolved by Scatchard analysis in both 13-day-old cerebellum and adult cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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Distribution of somatostatin receptors in the brain of the frog Rana ridibunda: correlation with the localization of somatostatin-containing neurons.
The biochemical characterization and anatomical distribution of somatostatin binding sites were examined in the brain of the frog Rana ridibunda, and the distribution of the receptors was compared with the location of somatostatin immunoreactive neurons. The pharmacological profile of somatostatin receptors was determined in the frog brain by means of an iodinated superagonist of somatostatin, [125I-Tyr0,DTrp8]S-14. Membrane-enriched preparations from frog brain homogenates were shown to contain high-affinity receptors (KD = 0.78 +/- 0.34 nM; Bmax = 103 + 12.7 fmoles/mg protein) with pharmacological specificity for [DTrp] substituted S14 and S28 analogs. The distribution of somatostatin-binding sites was studied by autoradiography on coronal sections of frog brain. Various densities of somatostatin receptors were detected in discrete areas of the brain. The highest concentration of binding sites was observed in the olfactory bulb, in the pallium, and in the superficial tectum. Moderate binding was observed in the striatum, amygdaloid complex, preoptic area, and cerebellum. Immunocytochemical studies of the distribution of somatostatin-28 (S28) related peptides were also conducted in the frog brain. Two antisera that recognize distinct epitopes of the somatostatin molecule have been used for immunohistochemical mapping of the peptide. Antiserum SS9 recognizes both S28 and somatostatin-14 (S14) and allowed the labelling of perikarya. Antiserum S320 recognizes the N-terminal fragment (1-12) resulting from enzymatic cleavage of S28. This latter antiserum, which does not cross-react with S28, stained mainly neuronal processes. At the infundibular level, however, both antisera stained cell bodies and fibers. Immunoreactive somatostatin-related peptides were detected in many areas of the frog brain. In the diencephalon, a heavy accumulation of perikarya and fibers was seen in the preoptic nucleus, the dorsal and ventral infundibular nuclei, and the median eminence. Immunoreactive perikarya were also observed in the telencephalon, especially in the pallium and in thalamic nuclei. Immunostained processes were detected in many telencephalic areas and in the tectum. There was good correlation between the distribution of somatostatin-immunoreactive elements and the location of somatostatin-binding sites in several areas of the brain, in particular in the median pallium, the tectum, and the interpeduncular nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
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Ontogeny of somatostatin receptors in the rat brain: biochemical and autoradiographic study.
The ontogeny of somatostatin receptors in the rat brain has been studied by both membrane binding assays and in vitro receptor autoradiographic techniques. High levels of somatostatin binding sites were detected in brain of 15-day-old fetuses (E15). The pharmacological characterization of somatostatin binding sites and the regulatory effect of GTP on somatostatin binding at E15 suggest that somatostatin recognition sites correspond to authentic receptors. The values of maximal binding showed important variations throughout pre- and postnatal development. Globally, a marked increase in the total binding capacity was observed between E15 and postnatal day 8 (P8), with a transient fall at birth and P1. After P8, the concentration of somatostatin receptors progressively decreased and the weaning imposed at P21 accentuated the decline of receptor concentration. Although the density of somatostatin binding sites varied considerably, KD values did not change during brain development. Autoradiographic studies showed marked differences in the distribution of somatostatin receptors during ontogenesis. In the cortex, the cortical plate and the subplate zone appeared to contain high densities of binding sites from E15 to P1. However, the cortical layer which exhibited the higher labelling was the intermediate zone, located just beneath the subplate zone. On the contrary, the germinal epithelium bordering the lateral ventricle appeared virtually devoid of somatostatin binding sites. This laminar distribution of binding sites in the cortex disappeared from P4 to P8, in coincidence with the evolution of the underlying histological organization. At these stages, a homogeneous distribution was observed in almost all cortical layers, contrasting with the distribution of somatostatin receptors in the adult, which was restricted to layers IV-VI. In the cerebellar cortex, autoradiographic labelling was first seen at E15. After birth, the density of somatostatin receptors increased dramatically between P4 and P13, while, at P23, the labelling vanished in most lobes of the cerebellum. Taken together, these results show the early appearance of somatostatin receptors in the rat brain. The high density of somatostatin receptors observed in proliferative or pre-migratory areas suggests that somatostatin may be an important factor involved in the organization of the central nervous system.
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Transient expression of somatostatin receptors in the rat cerebellum during development.
Somatostatin and somatostatin receptors have not been identified in adult rat cerebellum. In contrast, during the development, somatostatin-containing neurons have been visualized in the deep layers of the cerebellum. The present study shows that during ontogenesis, somatostatin receptors are present in close association with the external granule cell layer of the cerebellum. No correlation was found between the location of immunoreactive somatostatin and the distribution of somatostatin receptors. The disappearance of somatostatin receptors, from postnatal day 13 to 23, was concomitant with the involution of the external germinal layer.
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Autoradiographic study of somatostatin receptors in the rat hypothalamus: validation of a GTP-induced desaturation procedure.
The radiolabelled somatostatin analogs [125I-Tyr0,DTrp8]S14 and [Leu8,DTrp22,125I-Tyr25]S28 were used as radioligands to study the distribution of somatostatin receptors in the rat hypothalamus. Previous studies have detected very few somatostatin-binding sites in the hypothalamus using in vitro autoradiography. Since the lack of autoradiographic labelling has been ascribed to the occupancy of the receptors by endogenous ligands, we have developed a method using guanosine triphosphate (GTP) pretreatment to unmask somatostatin receptors. Preincubation of brain slices with 10(-6) M GTP, by desaturating the occupied receptors, made it possible to reveal the wide distribution of somatostatin-binding sites in the rat hypothalamus. Somatostatin-14 binding site populations were observed in numerous hypothalamic areas including the preoptic area where the receptors likely account for self-inhibition of somatostatin release, the supraoptic nucleus, the bed nucleus of the stria terminalis, the anterior hypothalamic nucleus, the perifornical area, the zona incerta and a mediolateral area located laterally to the ventromedian and dorsomedian nuclei and limited laterally by the mammillo-thalamic tract, the fornix and the optic tract. All structures showing S14-binding sites were labelled by the S28 radioligand. In addition, the paraventricular parvocellular nucleus contained exclusively S28-binding sites, which could be involved in the inhibitory effect of S28 on CRF-mediated endocrine and sympathetic responses. A moderate density of S28-preferring sites was also detected in the periventricular nucleus. In summary, GTP preincubation of brain slices appeared to be a useful technique to reveal multiple somatostatin receptors populations in the brain. The widespread distribution of somatostatin receptors in the hypothalamus is in total agreement with the variety of physiological effects of the somatostatin peptide family.
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