Biomedical subjects

E C Azmitia

Publications and source records attributed to E C Azmitia.

At least 37 records · Page 2Linked to original sources

PubMed1996

Neuro-glial neurotrophic interaction in the S-100 beta retarded mutant mouse (Polydactyly Nagoya). III. Transplantation study.

The hippocampus and caudo-dorsal cortex of the homozygote of polydactyly mutant mouse (Polydactyly Nagoya, Pdn/Pdn) were markedly reduced in S-100 beta positive astrocytes and serotonergic fibers as compared to the heterozygote (Pdn/+) and wild type (+/+) [39]. The Pdn/Pdn mice die within 2 days after birth, so it is impossible to examine postnatal changes. To demonstrate the developmental change of Pdn/Pdn hippocampal tissue, we transplanted hippocampal pieces of neonatal Pdn/Pdn and +/+ mice into the right and left hippocampus of the same adult +/+ mice, respectively, and immunocytochemically examined them. Two weeks after transplantation, +/+ hippocampal tissue contained a large number of glial fibrillary acidic protein (GFAP) and S-100 beta positive astrocytes and a number of serotonergic fibers. While Pdn/Pdn hippocampal tissue contained numerous GFAP positive astrocytes, S-100 beta positive astrocytes and serotonergic fibers were not observed. Two months after transplantation, GFAP and S-100 beta were expressed in the Pdn/Pdn hippocampal tissue similar to the +/+ tissue. Serotonergic fibers were distributed in the +/+ tissue, while no serotonergic fibers were observed in the Pdn/Pdn transplant tissue. In contrast, no difference was observed in the tyrosine hydroxylase positive fibers between Pdn/Pdn and +/+ grafts. The expression of 5-HT1A receptor-like immunoreactivity was higher in the +/+ tissue than that of Pdn/Pdn tissue. The present results suggest that the expression of S-100 beta in the astrocytes of early stage of transplantation is a critical for fiber ingrowth of serotonergic neurons and expressions of 5-HT1A receptor.

Animals↗

PubMed1996

5-HT1A receptor expression is modulated by corticosteroid receptor agonists in primary rat hippocampal culture.

The effects of corticosteroid receptor agonists on the expression of 5-HT1A receptor mRNA were measured in rat hippocampal cultures using in situ hybridization histochemistry. In our normal culture system, grown in serum and steroid-free media, moderate to heavy signal for 5-HT1A mRNA transcripts were detected in hippocampal neurons and glial cells. Aldosterone, a type I corticosteroid receptor agonist (10(-9) M), significantly reduced the expression of 5-HT1A mRNA both in neurons and glial fibrillary acidic protein (GFAP)-immunoreactive (IR) cells. The type II corticosteroid receptor agonist, Ru28362 (10(-8) M), also significantly decreased neuronal 5-HT1A mRNA expression. However, it was not as effective as aldosterone in reducing the label over GFAP-IR cells. These data indicate that corticosteroids may directly regulate the expression of hippocampal 5-HT1A receptors at the mRNA level in cultured hippocampal cells.

Aldosterone↗

PubMed1996

Enhanced synaptophysin immunoreactivity in rat hippocampal culture by 5-HT 1A agonist, S100b, and corticosteroid receptor agonists.

Serotonin (5-HT) has been shown to modulate brain maturation during development and adult plasticity. This effect in the whole animal may be due to activation of 5-HT1A receptors and a corresponding increases in S100b and corticosterone. Synaptophysin, an integral protein of the synaptic vesicle membrane that correlates with synaptic density and neurotransmitter release, is reduced by depletion of 5-HT in the cortex and hippocampus of the adult rat. Injections of a 5-HT1A agonist or dexamethasone can reverse the loss of synaptophysin immunoreactivity (IR). In this study we used morphometric analysis of synaptophysin-IR to study the effects of the 5-HT1A agonist, ipsapirone, and the neuronal extension factor, S100b on hippocampal neurons grown in a serum and steroid free media. Both compounds increased the synaptophysin-IR at doses previously established to be highly specific. Ipsapirone (10(-9)M) was more effective on neuronal cell bodies staining and S100b (10 ng/ml) was more effective in increasing the number of synaptophysin-IR varicosities on neuronal processes. In addition both types of corticosteroid receptor agonists, at previously established specific doses, Ru28362 (10(-8) M) and aldosterone (10(-9) M) produced smaller increases compared to control groups in both the cell body staining and the number of varicosities. The effect of these differentiating factors on the expression of synaptophysin-IR suggests multiple regulation sites for producing and maintaining pre-synaptic elements in the brain.

Animals↗

PubMed1996

Increased 5-HT1A receptor immunoreactivity in the rat hippocampus following 5,7-dihydroxytryptamine lesions in the cingulum bundle and fimbria-fornix.

Serotonin (5-HT) projections from the ascending raphe nuclei reach the dorsal hippocampus via the cingulum bundle (CB) and fimbria-fornix (FF). Microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the CB and FF produces a significant decrease in the density of 5-HT immunoreactive fibers in the hippocampus as early as 3 days postlesion (Zhou, F.C. and Azmitia, E.C. (1983) Brain Res. Bull., 373, 337-348). In the present study we used an anti-peptide antibody against the second extracellular loop of the 5-HT1A receptor and employed immunocytochemistry to examine changes in the expression and distribution of the 5-HT1A receptor in the hippocampus 14 days following administration of 5,7-DHT into the CB and FF. The density of 5-HT immunoreactive fibers was greatly reduced 14 days following the lesions. 5-HT1A immunoreactivity (IR) was localized to the proximal axon near the axon hillock of cells in the pyramidal cell layer of the cornu Ammonus and in the granule cell layer of the dentate gyrus. The intensity of 5-HT1A-IR was increased in the CA1 and dentate gyrus following 5,7-DHT lesions. Intensity in the CA3 also increased but not to a significant level. These findings demonstrate that 5-HT denervation in the hippocampus is followed by increased expression of the 5-HT1A receptor protein. These changes in receptor expression 14 days postlesion may represent adaptive changes by postsynaptic cells following reduced 5-HT innervation and may be the molecular basis for 5-HT1A receptor supersensitivity.

5,7-Dihydroxytryptamine↗

PubMed1996

Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells.

Activation of 5HT1A receptors produces many different physiologic responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170-186) antibody was produced that showed both high titer for peptide binding and immunocytochemical staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from our studies of Macaca fascicularis brains are presented. We observed two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also observed in the nucleus locus coeruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1-4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addition to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clinical implications of 5-HT1A cellular localization are briefly discussed.

Animals↗

PubMed1995

3,4-Methylenedioxymethamphetamine ('Ecstasy') promotes the translocation of protein kinase C (PKC): requirement of viable serotonin nerve terminals.

The metabolic effects of the neurotoxic, ring-substituted amphetamine 3,4-methylenedioxy-methamphetamine (MDMA or 'Ecstasy') were examined in vivo. In this study, we focused on the ability of MDMA to induce a translocation of the calcium and phospholipid-dependent protein kinase C (PKC) from the cytosol to the cortical plasma membrane. Two injections of MDMA (20 mg/kg; 10 h apart; s.c.) increased the density of membrane bound PKC sites by 48.0% over saline treated animals without mediating a significant change in ligand ([3H]phorbol 12,13 dibutyrate; [3H]PDBu) affinity. Longer drug treatments (8 x 20 mg/kg) induced a lasting (up to 5 days post-treatment) increase in the density of membrane-bound PKC. Prior destruction of cortical 5-HT nerve terminals with p-chloroamphetamine (PCA) prevents this effect and suggests that viable 5-HT uptake sites are essential for MDMA-induced PKC translocation. These results demonstrate that MDMA-induced PKC translocation is mediated by viable cortical 5-HT nerve terminals, and that prolonged kinase activation may contribute to MDMA-induced serotonergic neurotoxicity.

Animals↗

PubMed1995

Activation of glycogen phosphorylase by serotonin and 3,4-methylenedioxymethamphetamine in astroglial-rich primary cultures: involvement of the 5-HT2A receptor.

Neurotransmitters, neuropeptides, and ions regulate glycogen levels in the brain by modulating the activity of glycogen synthase (GSase) and glycogen phosphorylase (GPase). GPase is co-localized with glial fibrillary acidic protein (GFAP), an astroglia-specific marker, suggesting that glycogen is localized in astroglial cells. Additionally, functional serotonin (5-HT) receptors are found in both neurons and glia, and 5-HT is known to stimulate glycogenolysis. It is reported that 3,4-methylenedioxymethamphetamine (MDMA), a drug of abuse, stimulates the release and inhibits the reuptake of 5-HT, and selectively inhibits the activity of MAO-A. These biochemical consequences of MDMA lead to increased extra-cellular 5-HT levels. This study investigates the effects of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat brain. A histochemical method was designed to visualize active glycogen phosphorylase (GPase) in an astroglial-rich primary culture. Serotonin activated GPase in a concentration-dependent manner (100 nM-100 microM). Maximal activation by 5-HT was achieved by 50 microM and resulted in a 167% increase in the number of reactive sites (P < 0.001). MDMA(+) (500 nM-50 microM) directly stimulated GPase activity with maximal activation induced by 5 microM, which caused a 70% increase in the number of reactive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-dependent increase in the number of GPase reactive sites. Maximal stimulation by DOB occurred at 100 nM which increased the number of reactive sites by 166% (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗

PubMed1995

5-HT1A receptor localization on the axon hillock of cervical spinal motoneurons in primates.

Serotonin (5-HT) has direct and specific effects on the activity of spinal cord motoneurons. The 5-HT1A receptor has been shown to mediate motoneuron responses in spinal reflex pathways using the highly selective 5-HT1A receptor agonist 8-OH-DPAT. We have developed an antipeptide antibody that recognizes a specific region (the second external loop) of the 5-HT1A receptor. This 5-HT1A receptor antibody labels populations of neurons and glia in the primate cervical spinal cord. The highest receptor density is present in the superficial lamina of the dorsal horn, around the central canal, and on the axon hillock of large ventral horn motoneurons. The cellular labeling pattern on motoneurons shows a single, densely stained, tapering process emanating from the perikaryon. A more diffuse label is also present throughout the soma. Dendritic labeling was not apparent. These results suggest that post-synaptic 5-HT1A receptors may be involved in modulating spinal motoneuron activity at the key site of action potential initiation, the axon hillock.

Animals↗

PubMed1995

5-HT1A agonist and dexamethasone reversal of para-chloroamphetamine induced loss of MAP-2 and synaptophysin immunoreactivity in adult rat brain.

Serotonin and dexamethasone act as differentiating agents during development. Reducing circulating adrenal steroids or central 5-HT levels via adrenalectomy (ADX) or the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA), respectively, has been shown to have de-differentiating effects in the adult brain. Morphometric analysis of 5-HT, S100 beta, MAP-2 and synaptophysin immunoreactivity (IR) was used to follow the molecular plasticity of several brain regions after lesioning of 5-HT nerve terminals by para-chloroamphetamine (PCA; 2 x 10 mg/kg s.c.), a serotonin neurotoxin. Two weeks after PCA treatment we observed reductions of 5-HT, S100 beta, and MAP-2 IR in parietal and temporal cortex, temporal pole, hippocampus and hypothalamus. The reductions in MAP-2 and synaptophysin-IR were reversed by 3 days of treatment with dexamethasone (10 mg/l drinking water) or ipsapirone, a 5-HT1A agonist (1 mg/kg s.c.). The loss of S100-IR was reversed only by the 5-HT1A agonist. These results indicate that both dexamethasone and serotonin have effects on adult neuronal plasticity but may work via different mechanisms. The implications of these findings to the loss of synaptophysin and MAP-2 staining in Alzheimer's disease are discussed.

Age Factors↗

PubMed1995

Role of neuropeptide Y projection on the development of serotonergic innervation in the suprachiasmatic nucleus of the rat, shown by triple intraocular grafts.

In our previous paper, the intraocular double grafts of fetal mesencephalic raphe and suprachiasmatic nucleus (SCN) demonstrated that the serotonergic fibers from raphe tissue did not show a dense innervation of SCN [28]. To examine the influence of NPY innervation from lateral geniculate nucleus (LGN) on the development of serotonergic fibers in the SCN, fetal mesencephalic raphe, SCN and LGN tissues were transplanted together into the eye chamber of adult rat. 6 weeks after transplantation, triple grafts were immunohistochemically examined. The SCN cell cluster was recognized by vasoactive intestinal polypeptide (VIP)- and arginine vasopressin (AVP)-immunoreactive neurons and The SCN cell cluster also contained a large number of serotonin-immunoreactive fibers from raphe tissue and a moderate number of neuropeptide Y (NPY)-immunoreactive fibers from LGN tissue. The present results provide information on possible NPY-serotonin interactions in the developing SCN.

Animals↗

PubMed1995

Rapid serotonergic fiber sprouting in response to ibotenic acid lesion in the striatum and hippocampus.

Serotonergic (5-HT) sprouting occurs after damage of neighboring 5-HT or non-5-HT fibers. The sprouting signals appear to originate from the target tissue where neural trophic factors are secreted. In order to determine the cellular source of the trophic signal we currently report that removal of local neurons with a neurotoxin, ibotenic acid (IB), triggered a vigorous sprouting of 5-HT fibers in the striatum as early as 3 days after the lesion, which lasted throughout the entire length (21 days) of our study. The 5-HT fiber density in the injection site increased 10-fold in the striatum compared to the contralateral side, and the density of 5-HT varicosities increased 4-fold of normal. The 5-HT level in the striatum correspondingly increased on the lesion side. Three clear morphological concentric zones were formed by the lesion: acellular, aneuronal and outer zones. These zones represent the characteristic reorganization of astrocytes and neurons following an injection of IB. Devoid of any cells, the small acellular zone in the center of the injection site contained few 5-HT fibers. Devoid of neurons, the aneuronal zone contained reactive astrocytes and an abnormally high density of 5-HT fibers with increased staining of S-100. Containing neurons and astrocytes, the outer zone had a normal 5-HT fiber density. The induced 5-HT sprouting in the aneuronal zone strongly suggests that local neurons could provide a trophic factor, but that astrocytes would be the most plausible candidate. This is not an isolated case, IB injections in the hippocampus also induce a similar phenomenon.

Animals↗

PubMed1995

Serotonergic sprouting into transplanted C-6 gliomas is blocked by S-100 beta antisense gene.

S-100 beta, a calcium binding protein produced by astrocytes, has been proposed to be a neuronotropic agent. In order to test the tropic effects of S-100 beta in vivo, the technique of cell transplantation was used. C6 glioma cells and C6 cells containing a S-100 beta antisense gene (C6AS) were transplanted into contralateral hippocampi. 5-HT immunoreactive, varicose fibers with a normal appearance penetrated into the glioma mass and were seen in high density around the C6 cell mass. However, 5-HT fibers with enlarged, abnormal varicosities were seen bordering C6AS tissue and were very rarely observed within the C6AS cell mass. Extracellular S-100 beta from normal C6 cells may function as a growth factor on sprouting serotonergic fibers.

Animals↗

PubMed1994

Dexamethasone reverses adrenalectomy-induced neuronal de-differentiation in midbrain raphe-hippocampus axis.

Differentiation leads to specific morphological and biochemical characteristics. We examined whether epigenetic factors (e.g., glucocorticoids) are required to maintain neuronal differentiation in the adult brain. In the midbrain, adrenalectomy (ADX) (1-2 wk) reduced the size of tryptophan hydroxylase (WH)-immunoreactive (IR) neurons. ADX rats exposed to short-term (24-72-h) dexamethasone (ST-DEX) in the drinking saline (10 mg/l) showed an increase in WH protein, somal area and dendritic size of WH-IR neurons. In the hippocampus, ADX for 2-3 mo (long-term; LT) reduced Nissl staining, calbindin (CBD)-IR and 5-HT1A receptor mRNA in the granular cell layer, and the size of the molecular layer and its CBD-IR dendrites. Small vimentin (Vim)-IR glial cells emerged in the granular layer. ST-DEX after LT-ADX rapidly induced a recovery of 5-HT1A mRNA, Nissl labeling and CBD-IR in the granule cell layer. In the molecular layer, there was an increase in the area and in the number of CBD-IR dendrites. Furthermore, the Vim-IR glial cells were enlarged in size and branching. The rate of cell proliferation was studied in these animals. Immunostaining with antibodies against proliferating cell nuclear antigen (PCNA) and use of bromouridine argue against enhanced neurogenesis after ST-DEX in LT-ADX. We propose that glucocorticoids induce and maintain differentiation of serotonergic and CBD-IR neurons in the midbrain-hippocampal axis. A neuronotrophic role for the glial 5-HT1A receptor is suggested.

Adrenalectomy↗

PubMed1994

Specificity versus redundancy of melanocortins in nerve regeneration.

The results of the present study demonstrate that administration of the ACTH-(4-9) analogue Org 2766 acutely enhances behavioral, morphological, and biochemical recovery after nigrostriatal destruction. Animals treated with Org 2766 (10 micrograms/kg every 24 hr) demonstrated an acceleration of denervation supersensitivity and a significantly decreased ipsilateral rotational response, as compared to their saline counterparts. Upon evaluation of the mesolimbic DA system using open field behavior, peptide-treated rats demonstrated a compensatory response in their rearing behavior. Furthermore, tyrosine hydroxylase immunocytochemical analysis indicated an enhanced staining in the Org 2766-treated groups. This evaluation was confirmed and quantified using specific high-affinity dopamine uptake. The brains of animals treated with Org 2766 maintained higher uptake levels, suggesting a greater fiber density than the saline-treated animals. Although recovery via reinnervation is very unlikely in this short period of time, improved recovery may be the result of a protective effect of Org 2766 after administration of 6-OHDA into the substantia nigra. Thus, it appears that Org 2766 provides the rapid effects in this system, by both accelerating some compensatory mechanisms necessary for functional recovery and promoting cell survival by providing neuronal protection. However, it does not appear that this protection is due to NMDA receptor manipulation. Org 2766 neither mimicked the NMDA antagonist MK-801 behaviorally nor biochemically in binding displacement studies. Interestingly, other studies have suggested that only the full ACTH molecule, and fragments larger than ACTH-(1-17), demonstrated binding activity at micromolar concentrations, whereas the shorter, noncorticotropic fragments were either less active or inactive (Table 2). As for ACTH-(4-10) immunoreactivity, it appears that this neurotrophic fragment of ACTH reappears in adults following injury to the nigrostriatal system. In addition, the systemically administered ACTH-(4-9) analogue, Org 2766, seems to be gaining access to the CNS, but is only effective in the injured system. Therefore, based on the immunocytochemical localization of the ACTH-(4-10) fragment in neonatal brains and in the injured adult rat CNS, the interesting possibility may be raised that endogenous ACTH peptides appear during both ontogeny and regeneration. These studies demonstrate once again that biological responses to the family of ACTH/MSH peptides depend on the specific peptide fragment administered, its dosage, and the timing of the administration. Consequently, since early intervention is of vital importance in CNS recovery processes, synergistic administration of ACTH fragments and other neurotrophic agents may offer a viable approach with which to combat degeneration in the CNS.

Adrenocorticotropic Hormone↗

PubMed1994

Prenatal cocaine decreases the trophic factor S-100 beta and induced microcephaly: reversal by postnatal 5-HT1A receptor agonist.

In utero exposure to cocaine results in neurobehavioral abnormalities in both clinical and laboratory studies. Cocaine administration from embryonic day 13 to parturition disrupts the distribution of S-100-positive astrocytes in the hippocampus and subplate region of the cortex in cocaine-exposed animals. Postnatal treatment with ipsapirone, a 5-HT1A agonist, shown to stimulate glial release of S-100, alleviated the cellular disruptions and growth retardation caused by prenatal cocaine exposure.

Animals↗

PubMed1994

In vitro release of [3H]5-hydroxytryptamine from fetal and maternal brain by drugs of abuse.

Cortical synaptosomes were prepared from pregnant dams (GD-17) and rat fetuses (ED-17), loaded with [3H]5-HT and assayed to evaluate release mediated by cocaine (COC), fenfluramine (FEN) and 3,4-methylenedioxymethamphetamine (MDMA). COC and FEN elicited a high-affinity (10(-9) M) release response in fetal tissue which was not apparent in the dam. MDMA-induced release was similar in magnitude in both tissue types. Consequently, the release of 5-HT from developing neurons may be one mechanism by which COC and FEN elicit their teratogenetic effects in utero.

3,4-Methylenedioxyamphetamine↗

PubMed1994

Neuro-glial neurotrophic interaction in the S-100 beta retarded mutant mouse (Polydactyly Nagoya). I. Immunocytochemical and neurochemical studies.

The homozygote of a mouse strain with genetic polydactyly (Polydactyly Nagoya; Pdn) shows several brain abnormalities, and significant decrease of S-100 beta in the brain. In order to clarify the effects of the retarded production of S-100 beta on the development of monoaminergic neuronal systems and supporting glial cells, immunocytochemical studies of tyrosine hydroxylase (TH), serotonin (5-HT), S-100 beta and glial fibrillary acidic protein (GFAP). In addition, high-performance liquid-chromatography (HPLC) measurements of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) of homozygote (Pdn/Pdn) mouse were examined, and the results were compared with those of other genotypes; heterozygote (Pdn/+) and wild type (+/+) mice. In all types of mice, S-100 beta positive cells and serotonergic fibers were widely distributed throughout the brains and serotonergic cell bodies were located in the brainstem. However, the hippocampus and caudo-dorsal cortex of Pdn/Pdn mouse were markedly reduced in S-100 beta positive cells and in serotonergic fibers. Furthermore, abnormal distribution of GFAP positive cells and fibers were observed in the neocortex and hippocampus of Pdn/Pdn brain. No differences were seen in the distribution of TH neurons or fibers distribution. In the HPLC study, the content of 5-HT and 5-HIAA of the hippocampus and cortex of Pdn/Pdn mouse was lower than those of Pdn/+ and +/+ mice. The present results suggest that the developmental defect of serotonergic fibers in the Pdn mutant mouse is correlate to the deficiency of S-100 beta in the astrocyte of this mutant.

Animals↗

PubMed1994

Neuro-glial neurotrophic interaction in the S-100 beta retarded mutant mouse (Polydactyly Nagoya). II. Co-cultures study.

The homozygote of a mouse strain with genetic polydactyly (Polydactyly Nagoya, Pdn) shows several brain abnormalities, and significant decrease of S-100 beta in the brain [17]. An accompanying paper [18] demonstrates that the hippocampus and caudo-dorsal cortex of homozygote (Pdn/Pdn) mouse were markedly reduced in S-100 beta positive astrocytes and serotonergic fibers, and the content of 5-HT and 5-HIAA of hippocampus and cortex of Pdn/Pdn mouse was lower than those of heterozygote (Pdn/+) or wild type (+/+) mice. To further clarify the effects of target tissues from different type brains on the development of serotonergic neurons, raphe neurons from Pdn/Pdn or +/+ newborn mice were co-cultured with hippocampus or cortex of +/+ or Pdn/Pdn newborn mice. The growth of the serotonergic neurons in the mesencephalic raphe tissue dissociated cultures was estimated by measuring the specific uptake of [3H]5-HT. The development of both genotypes (Pdn/Pdn and +/+) of serotonergic neurons was enhanced by co-cultures with target tissues (hippocampus and cortex) of +/+ brain. This effect was not observed in the co-cultures with Pdn/Pdn brain as a source of target tissue. The present results support the idea that the developmental defect of serotonergic fibers in the Pdn mutant mouse is caused by the deficiency of S-100 beta in the astrocyte of this mutant, and suggest that S-100 beta is a serotonergic growth factor. This mutant mouse is a useful in vivo model to study neural-glial neurotrophic interactions.

Animals↗