Brain-derived neurotrophic factor (BDNF) protects cultured rat cerebellar granule neurons against glucose deprivation-induced apoptosis

In the present study, cell death induced by glucose deprivation in primary cultures of cerebellar granule neurons was examined. Glucose deprivation-induced apoptotic cell death was demonstrated using the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method and DNA fragmentation assays. When the effects of different neurotrophins on the survival of cerebellar granule neurons after glucose deprivation were assessed, BDNF, but not NT-3 or NGF, was found to protect cerebellar granule neurons against glucose deprivation-induced cell death. In addition, BDNF treatment increased c-Fos immunoreactivity in the cerebellar granule neurons. These results are consistent with the hypothesis that neuronal death due to glucose deprivation has a significant apoptotic component and that neurotrophins can protect against hypoglycemic damage.     

Brain-derived neurotrophic factor modulates the development of the dopaminergic network in the rodent retina

Dopaminergic cells in the retina express the receptor for brain-derived neurotrophic factor (BDNF) (). To investigate whether BDNF can influence the development of the retinal dopaminergic pathway, we performed intraocular injections of BDNF during the second or third postnatal week and visualized the dopaminergic system with tyrosine hydroxylase (TH) immunohistochemistry. Both regimens of BDNF treatment caused an increase in TH immunoreactivity in stratum 1 and stratum 3 of the inner plexiform layer (IPL). D2 dopamine receptor immunoreactivity, a presynaptic marker of dopaminergic cells (), was also increased in stratum 1 and stratum 3 of the inner plexiform layer. These data suggest that BDNF causes sprouting of dopaminergic fibers in the inner plexiform layer. Other neurochemical systems, for example, the cholinergic amacrine cells, remained unaffected. Similar effects were observed after injections of neurotrophin-3 and neurotrophin-4, but not nerve growth factor. Analysis of whole-mounted TH-immunolabeled retinae revealed hypertrophy of dopaminergic cells (+41% in soma areas; p < 0.01) and an increase of labeled dopaminergic varicosities in stratum 1 of the IPL (+51%; p < 0.01) after BDNF treatment. The opposite was observed in mice homozygous for a null mutation of the bdnf gene: dopaminergic cells were atrophic (-22.5% in soma areas; p < 0.05), and the density of TH-positive varicosities in stratum 1 was reduced (57%; p < 0.01). We conclude that BDNF controls the development of the retinal dopaminergic network and may be particularly important in determining the density of dopaminergic innervation in the retina.     

Brain-derived neurotrophic factor and neurotrophin-4 increase neurotrophin-3 expression in the rat hippocampus

Hippocampal levels of mRNA encoding nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are rapidly induced by enhanced neuronal activity following seizures and glutamate or muscarinic receptor activation. However, the levels of neurotrophin-3 (NT-3) mRNA acutely decrease after limbic seizures suggesting that a different mode of regulation may exist for these neurotrophins. Here we show that BDNF and neutrotrophin-4 (NT-4), but not NT-3 itself, up-regulate NT-3 mRNA in cultured hippocampal neurons. In the rat hippocampus, the muscarinic receptor agonist, pilocarpine increased BDNF mRNA levels rapidly and those of NT-3 with a delay of several hours. Injection of BDNF into neonatal rats elevated NT-3 mRNA in the hippocampus which demonstrates that BDNF is able to enhance NT-3 expression in vivo. The regulation of NT-3 by BDNF and NT-4 enlargens the neurotrophic spectrum of these neurotrophins to include neuron populations responsive primarily to NT-3.     

Alpha isoform of calcium-calmodulin dependent protein kinase II (CAM II kinase-alpha) restricted to excitatory synapses in the CA1 region of rat hippocampus

Pre-embedding immunoperoxidase staining for CAM II kinase-alpha and post-embedding immunogold staining for glutamate and GABA, were used to reveal the subcellular distribution of CAM II kinase-alpha at transmitter-characterized synapses in the CA1 region of rat hippocampus. Immunoelectron microscopy showed that the majority of CAM II kinase-alpha-immunostained neuronal profiles were dendritic spines presumably derived from pyramidal cells. CAM II kinase-alpha immunoreactivity was mainly localized in postsynatic densities associated with glutamatergic axon terminals. No CAM II kinase-alpha immunoreactivity was detected in GABA-immunoreactive profiles or at GABAergic synapses. This study provides morphological evidence that CAM II kinase-alpha is involved only in excitatory neuronal transmission in the CA1 region. The enzyme is unlikely to be involved in plasticity at GABA synapses.     

NMDA receptor dependence of mGlu-mediated depression of synaptic transmission in the CA1 region of the rat hippocampus

1. The depression of synaptic transmission by the specific metabotropic glutamate receptor (mGlu) agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD) was investigated in area CA1 of the hippocampus of 4-10 week old rats, by use of grease-gap and intracellular recording techniques. 2. In the presence of 1 mM Mg2+, (1S,3R)-ACPD was a weak synaptic depressant. In contrast, in the absence of added Mg2+, (1S,3R)-ACPD was much more effective in depressing both the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of synaptic transmission. At 100 microM, (1S,3R)-ACPD depressed the slope of the field excitatory postsynaptic potential (e.p.s.p.) by 96 +/- 1% (mean +/- s.e.mean; n = 7) compared with 23 +/- 4% in 1 mM Mg(2+)-containing medium (n = 17). 3. The depressant action of 100 microM (1S,3R)-ACPD in Mg(2+)-free medium was reduced from 96 +/- 1 to 46 +/- 6% (n = 7) by the specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5; 100 microM). 4. Blocking both components of GABA receptor-mediated synaptic transmission with picrotoxin (50 microM) and CGP 55845A (1 microM) in the presence of 1 mM Mg2+ also enhanced the depressant action of (1S,3R)-ACPD (100 microM) from 29 +/- 5 to 67 +/- 6% (n = 6). 5. The actions of (1S,3R)-ACPD, recorded in Mg(2+)-free medium, were antagonized by the mGlu antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). Thus, depressions induced by 30 microM (1S,3R)-ACPD were reversed from 48 +/- 4 to 8 +/- 6% (n = 4) by 1 mM (+)-MCPG. 6. In Mg(2+)-free medium, a group I mGlu agonist, (RS)-3, 5-dihydroxyphenylglycine (DHPG; 100 microM) depressed synaptic responses by 74 +/- 2% (n = 18). In contrast, neither the group II agonists ((2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine; L-CCG-1; 10 microM; n = 4) and ((2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine; DCG-IV; 100 nM; n = 3) nor the group III agonist ((S)-2-amino-4-phosphonobutanoic acid; L-AP4; 10 microM; n = 4) had any effect. 7. The depolarizing action of (1S,3R)-ACPD, recorded intracellularly, was similar in the presence and absence of Mg(2+)-AP5 did not affect the (1S,3R)-ACPD-induced depolarization in Mg(2+)-free medium. Thus, 50 microM (1S,3R)-ACPD induced depolarizations of 9 +/- 3 mV (n = 5), 10 +/- 2 mV (n = 4) and 8 +/- 2 mV (n = 5) in the three respective conditions. 8. On resetting the membrane potential in the presence of 50 microM (1S,3R)-ACPD to its initial level, the e.p.s.p. amplitude was enhanced by 8 +/- 3% in 1 mM Mg2+ (n = 5) compared with a depression of 37 +/- 11% in the absence of Mg2+ (n = 4). Addition of AP5 prevented the (1S,3R)-ACPD-induced depression of the e.p.s.p. (depression of 4 +/- 5% (n = 5)). 9. It is concluded that activation by group 1 mGlu agonists results in a depression of excitatory synaptic transmission in an NMDA receptor-dependent manner.     

Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1

Although neurotrophins have traditionally been regarded as neuronal survival factors, recent work has suggested a role for these factors in synaptic plasticity. In particular, brain-derived neurotrophic factor (BDNF) rapidly enhances synaptic transmission in hippocampal neurons through trkB receptor stimulation and postsynaptic phosphorylation mechanisms. Activation of trkB also modulates hippocampal long-term potentiation, in which postsynaptic N-methyl-D-aspartate glutamate receptors play a key role. However, the final common pathway through which BDNF increases postsynaptic responsiveness is unknown. We now report that BDNF, within 5 min of exposure, elicits a dose-dependent increase in phosphorylation of the N-methyl-D-aspartate receptor subunit 1. This acute effect occurred in hippocampal synaptoneurosomes, which contain pre- and postsynaptic elements, and in isolated hippocampal postsynaptic densities. Nerve growth factor, in contrast, caused no enhancement of phosphorylation. These results suggest a potential mechanism for trophin-induced potentiation of synaptic transmission.     

Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1

Glutamatergic fast synaptic transmission is known to be altered with age in a region-specific manner in hippocampus of memory-impaired old rats. In the present experiment, presynaptic fiber potentials and non-N-methyl-D-aspartate (NMDAR) and NMDAR-mediated synaptic responses in CA1 were compared in three ages of behaviorally characterized male F-344 rats. In the CA1 region, old rats showed approximately equivalent reductions in non-NMDAR- and NMDAR-excitatory postsynaptic potential amplitudes for a given size of presynaptic fiber potential. There was no change in magnitude of the presynaptic response itself at any stimulus level. These results are consistent with the hypothesis that there is a reduction in the number of Schaffer collateral synapses per presynaptic axon. This pattern of results in CA1 is very different from what is known to occur at the perforant path-granule cell synapse. In fascia dentata the non-NMDAR-mediated excitatory postsynaptic potential is increased in amplitude, although the NMDAR-mediated excitatory postsynaptic potential is reduced for a given presynaptic input. These data suggest that age-related functional alterations in neurotransmitter receptor subtypes occur differentially between closely-related anatomical subregions.     

Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals 相似文献   

An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M

The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization.     

Pharmacological modulation of GABA(A) receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus

It is unclear whether GABA(A) receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP(A)s and DPSP(A)s, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA(A) receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA(A) receptor ligands, on each response. The GABA uptake inhibitor NNC 05-711 (10 microM) enhanced whereas bicuculline (10 microM) inhibited both IPSP(A)s and DPSP(A)s. (-)-Baclofen (5 microM), [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO; 0.5 microM), and carbachol (10 microM) caused substantial depressions (up to 99%) of DPSP(A)s that were reversed by CGP 55845A (1 microM), naloxone (10 microM) and atropine (5 microM), respectively. In contrast, 2-chloroadenosine (CADO; 10 microM) only slightly depressed DPSP(A)s. Quantitatively, the effect of each agonist was similar to that reported for IPSP(A)s. The neurosteroid ORG 21465 (1 - 10 microM), the anaesthetic propofol (50-500 microM), the barbiturate pentobarbitone (100-300 microM) and zinc (50 microM) all enhanced DPSP(A)s and IPSP(A)s. The benzodiazepine (BZ) agonist flunitrazepam (10-50 microM) and inverse agonist DMCM (1 microM) caused a respective enhancement and inhibition of both IPSP(A)s and DPSP(A)s. The BZomega1 site agonist zolpidem (10-30 microM) produced similar effects to flunitrazepam. The anticonvulsant loreclezole (1-100 microM) did not affect either response. These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP(A)s and DPSP(A)s by activating GABA(A) receptors that are subject to similar allosteric modulation.     

L-deprenyl (selegiline) decreases excitatory synaptic transmission in the rat hippocampus via a dopaminergic mechanism

The effect of L-deprenyl (selegiline) on the excitatory synaptic transmission was characterized in the CA1 neurons of rat hippocampal slices by using a intracellular recording technique. Superfusion of L-deprenyl (0.1-10 microM) reversibly decreased the EPSP, which was evoked by orthodromic stimulation of the Schaffer collateral-commissural afferent pathway in a concentration-dependent manner. The sensitivity of postsynaptic neurons to the glutamate receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate, was not affected by L-deprenyl (1 microM) pretreatment. In addition, L-deprenyl (1 microM) clearly increased the magnitude of paired-pulse facilitation regardless of the interstimulus intervals of 20 to 300 msec used. The ability of L-deprenyl to decrease the EPSP amplitude was not observed in the dopamine-depleted rats. Pargyline and 4-phenylpyridine, the monoamine oxidase type B inhibitors, mimicked the depressant effect of L-deprenyl on the EPSP. Moreover, the reduction of L-deprenyl (1 microM) on the EPSP amplitude was specifically antagonized by sulpiride (0.01-0.1 microM), a selective dopamine D2 receptor antagonist. However, the dopamine D1 receptor antagonist, SKF-83566 (1-10 microM), did not significantly affect L-deprenyl's action. These results indicate that the monoamine oxidase type B inhibitory ability leading to an increase of the dopaminergic tonus in the hippocampus is involved in the L-deprenyl-induced depression of excitatory synaptic transmission in the CA1 region of the rat hippocampus. Moreover, application of L-deprenyl (1 and 10 microM) also reversibly suppressed the epileptiform activity evoked by picrotoxin.     

Dopaminergic transmitter up-regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) synthesis in mouse astrocytes in culture

We developed a highly sensitive enzyme immunoassay (EIA) system for brain-derived neurotrophic factor (BDNF) based on a biotin-streptavidin detection system capable of measuring concentrations as low as 1.0 pg/ml with high reproducibility. Using this EIA system, we examined the effect of dopaminergic transmitters such as dopamine and epinephrine on BDNF synthesis in mouse astrocytes in culture. These drugs had a stimulating effect on BDNF synthesis and showed a stronger promoting activity toward BDNF synthesis than toward nerve growth factor (NGF) synthesis. This is the first reported study in which BDNF synthesis was shown to be strongly stimulated by dopaminergic transmitter in mouse astrocytes. Then, we measured BDNF levels in the developing rat brain (striatum and midbrain). BDNF levels were relatively higher than NGF and NT-3 levels in these tissues. The BDNF level was high at the early stage in which neurons were proliferating, migrating, and differentiating, and it generally decreased as these cells matured.     

Leukemia inhibitory factor modulates interleukin-1beta-induced activation of the hypothalamo-pituitary-adrenal axis

We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1beta (IL-1beta; 0.1-10.0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h, and still persistently elevated above the baseline after 8 h. This effect of IL-1beta on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1beta antibody (10 microg/ml). Tumor necrosis factor-alpha (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1beta (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, i.p. injection of 100 ng IL-1beta increased plasma ACTH and corticosterone levels after 1 h (P < 0.02). In addition, pituitary LIF mRNA content was increased for up to 2 h in response to IL-1beta. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a deleted LIF gene (-/-) exhibited decreased plasma ACTH (631 +/- 61 vs. 376 +/- 50 pg/ml; P < 0.01) and corticosterone (783 +/- 85 vs. 433 +/- 51 ng/ml; P < 0.01) levels 1 h after i.p. IL-1beta administration. In conclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1beta and tumor necrosis factor-alpha. The attenuated hypothalamo-pituitary-adrenal response to IL-1beta in LIF knockout mice indicates that the effect of IL-1beta on ACTH secretion is modulated by LIF. Thus, LIF appears to function as an immune-neuroendocrine modulator signaling the hypothalamo-pituitary-adrenal axis.     

Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats

OBJECTIVE: In addition to the physical symptoms of galactorrhoea and amenorrhoea, hyperprolactinaemia in women is also reported to be associated with psychological symptoms. Previous studies have found an increased incidence of depression, anxiety and hostility in female patients with hyperprolactinaemia. In this study, psychological symptoms were assessed in a large population of patients and symptom scores were compared between patients with definite evidence of pituitary adenoma on high-resolution CT scanning and those without, who were presumed to have idiopathic or 'functional' hyperprolactinaemia. DESIGN: Postal survey: population-control study of female patients with hyperprolactinaemia. PATIENTS: Sixty-five women with hyperprolactinaemia were compared with a control group of 26 women with normoprolactinaemic pituitary disease (acromegaly or nonfunctioning pituitary adenoma). The hyperprolactinaemic patients were subdivided according to whether a pituitary adenoma was visible on high-resolution CT scanning (39 patients) or whether they had normal CT scans, in which case they were categorized as having idiopathic or 'functional' hyperprolactinaemia (26 patients). MEASUREMENTS: Patients were sent 2 questionnaires, the Hospital Anxiety and Depression (HAD) Scale and the 90-item Symptom Checklist (SCL-90), to assess psychological wellbeing. RESULTS: Overall, 54% of hyperprolactinaemic patients were found to have definite or borderline anxiety as judged by HAD scores, compared with 27% of normoprolactinaemic control patients. Those with normal CT scans were significantly more likely to have definite or borderline anxiety (73% of patients) than those with CT evidence of a pituitary tumour causing their hyperprolactinaemia (41%, P < 0.003), despite similar levels of serum prolactin. A similar increased proportion of hyperprolactinaemic patients scored highly on the anxiety component of the SCL-90, although mean scores were not different from controls. No differences were seen in scores for depression, but both subgroups of hyperprolactinaemic patients scored more highly than controls for hostility on the SCL-90 questionnaire. CONCLUSION: These findings confirm the presence of significant anxiety in a proportion of women with hyperprolactinaemia. Hyperprolactinaemic women with no abnormality on CT scans displayed more psychological distress than those with definite pituitary microadenomas. These results may provide insight into the pathogenesis of 'functional' hyperprolactinaemia.     

Endogenous adenosine attenuates long-term depression and depotentiation in the CA1 region of the rat hippocampus

We describe a series of 144 cases of leptospirosis diagnosed in 1989 in New Caledonia. The incidence rate was 90 per 100,000 person-years, with a specific mortality rate of 4% patients. Those affected (100 males, 44 females) were mainly aged 20 to 40 years. Incidence in rural areas (112 per 100,000 person-years) was seven times higher than in urban settlements. Two periods with higher incidence were noticed corresponding to highest rainfall. Twenty-nine of the cases occurred in individuals with professions commonly associated with leptospirosis. Contacts with rats, dogs and ditch or river water were the most frequently mentioned. The clinical expression of the disease was polymorphic: 60% of the patients had mild symptoms, 40% were acute forms including Weil's disease. Of 57 hospitalized, 23% were admitted with an initial diagnosis of dengue, and 37% with leptospirosis. Main clinical syndromes were: icterus and/or renal syndrome in 50% of patients, cardiac syndrome in 65%, acute myalgies in 58% and pulmonary syndrome in 50%. Although hemorrhages were uncommon (17%), 40% of the cases demonstrated thrombocytopenia (< 50,000/m3). Pancreatic involvement with hyperamylasemia was evidenced in 50% of cases. Twelve serogroups of Leptospira were implicated, Icterohaemorragiae predominated (41%), but was not associated with severe forms. In New Caledonia, like in all tropics, leptospirosis must be considered as an environmental diseases, professional activities being just an additional risk factor. Use of serology as a reliable tool for confirmation of cases in areas of high environmental contamination is discussed.     

Brain-derived neurotrophic factor promotes the differentiation of various hippocampal nonpyramidal neurons, including Cajal-Retzius cells, in organotypic slice cultures

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system, where its function is poorly understood. The aim of this study was to investigate the effects of BDNF on the differentiation of hippocampal nonpyramidal neurons using organotypic slice cultures prepared from postnatal rats. The application of BDNF induced an increase in immunostaining for the microtubule-associated protein (MAP)-2 in non-pyramidal neurons of the stratum oriens. BDNF promotes the elongation of the dendrites of these neurons, as demonstrated by analysis after biocytin labeling. Calbindin-D- and calretinin-containing subgroups of nonpyramidal cells in the stratum oriens were responsive to BDNF but not to nerve growth factor, as shown by an increase in the number of neurons immunostained for these proteins. BDNF also induced an increase in neuropeptide Y immunostaining of stratum oriens neurons. In contrast, BDNF had no effect on parvalbumin immunostaining, despite the fact that these cells express the BDNF receptor trkB. In addition, BDNF increased calretinin immunoreactivity in Cajal-Retzius cells situated around the hippocampal fissure. The Cajal-Retzius neurons persisted in slices beyond the time at which they degenerate in vivo. However, BDNF is not required for the survival of these cells, because they also persisted in slices from BDNF knock-out mice. The present results indicate that BDNF exerts an effect on the morphology of stratum oriens nonpyramidal cells and their calcium-binding protein levels. BDNF also regulates the calretinin content of Cajal-Retzius cells but is not necessary for their survival.     

Reconstitution of the response to leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in hepatoma cells

Ciliary neurotrophic factor (CNTF) has been described as a neuro-active cytokine that shares functional similarities with the leukemia inhibitory factor (LIF). We demonstrate here that, like LIF, CNTF stimulates expression of acute phase plasma proteins in rat H-35 hepatoma cells. Transfection of the LIF receptor into Hep3B hepatoma cells reconstituted LIF and oncostatin M regulation of acute phase plasma protein genes. Co-expression of the LIF receptor and the CNTF receptor, but not expression of either subunit alone, generated CNTF responsiveness in Hep3B cells, suggesting cooperativity of these receptor subunits. Evidence is presented for direct interaction of the LIF receptor with the intracellular signal transduction machinery.     

Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus

Long-term depression of synaptic transmission was induced following the prior induction of long-term potentiation in the CA1 region of rat hippocampal slices. We show that the induction of this form of synaptic depression can be prevented by (+)-alpha-methyl-4-carboxyphenylglycine, a selective antagonist of metabotropic glutamate receptors.     

Reciprocal suppression of the AMPA and NMDA components of the excitatory postsynaptic potentials in the CA1 area of the rat hippocampus in vitro

The interaction between N-methyl-d-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-dependent components of excitatory postsynaptic potentials (EPSP) was studied in rat hippocampal slices. Responses evoked by stimulation of the collateral commissural fibers were recorded in the radial layer of the CA1 area. Contribution of the NMDA component was changed by application of solutions with different concentrations of magnesium. In solutions with low magnesium concentration, when both AMPA and NMDA components contribute significantly to EPSP, suppression of one of the components by application of selective antagonist resulted in increase in the area of another component. Thus, the sum of pharmacologically isolated AMPA and NMDA components was significantly higher than the control EPSP. For example, at 0.1 mM of magnesium in the extracellular solution the sum of the components was 340 +/- 120% of the control EPSP (p < 0.01, N = 6). The data imply that under the control conditions the EPSP components suppress each other. The mutual suppression of the AMPA and NMDA component of the EPSP can be an important factor which influences the conductivity and plastic properties of central glutamatergic synaptic pathways.