Search

Background: Conventionally, the first step in analyzing the large and high-dimensional data sets measured by microarrays is visual exploration. Dendrograms of hierarchical clustering, selforganizing maps (SOMs), and multidimensional scaling have been used to visualize similarity relationships of data samples. We address two central properties of the methods: (i) Are the visualizations trustworthy, i.e., if two samples are visualized to be similar, are they really similar? (ii) The metric. The measure of similarity determines the result; we propose using a new learning metrics principle to derive a metric from interrelationships among data sets. Results: The trustworthiness of hierarchical clustering, multidimensional scaling, and the selforganizing map were compared in visualizing similarity relationships among gene expression profiles. The self-organizing map was the best except that hierarchical clustering was the most trustworthy for the most similar profiles. Trustworthiness can be further increased by treating separately those genes for which the visualization is least trustworthy. We then proceed to improve the metric. The distance measure between the expression profiles is adjusted to measure differences relevant to functional classes of the genes. The genes for which the new metric is the most different from the usual correlation metric are listed and visualized with one of the visualization methods, the self-organizing map, computed in the new metric. Conclusions: The conjecture from the methodological results is that the self-organizing map can be recommended to complement the usual hierarchical clustering for visualizing and exploring gene expression data. Discarding the least trustworthy samples and improving the metric still improves it.

Atrial natriuretic peptide (ANP) binding sites were measured by quantitative autoradiography in the supraoptic and paraventricular nuclei and in the subfornical organ of hypophysectomized, adrenalectomized, and genetically vasopressin-deficient (Brattleboro) rats. Hypophysectomized and Brattleboro rats had significantly higher numbers of ANP binding sites in the supraoptic nucleus and in the magnocellular subdivision of the paraventricular nucleus than their respective controls. ANP binding density was also increased in the parvocellular subdivision of the paraventricular nucleus in hypophysectomized rats and in the subfornical organ of homozygous Brattleboro rats. When homozygous Brattleboro rats were treated with vasopressin, the density of ANP binding sites was restored to control level in the subfornical organ but not in the supraoptic or paraventricular nuclei. Adrenalectomy did not influence ANP binding in the brain areas studied. Increased ANP binding density in Brattleboro rats and after hypophysectomy in the nuclei in which vasopressin neurons are located suggest that ANP binding sites may represent physiologically active receptors and may mediate the inhibitory action of ANP on vasopressin secretion.

Substance P binding sites were characterized in brain nuclei of young (4-wk-old) and adult (16-wk-old) spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) control rats by quantitative autoradiography. Young SHR presented higher affinity constants (KA) than young WKY. The changes were restricted to the locus coeruleus, the area postrema, the dorsal motor nucleus of the vagus, and to discrete areas located in lobes 9 and 10 of the vermis cerebelli of SHR. There were no differences in the maximal binding capacity (Bmax) except in the nucleus ambiguus where the Bmax was lower than in WKY. Conversely, the number of substance P binding sites was higher in the locus coeruleus, the nucleus tegmentalis dorsalis, the nucleus ambiguus, the dorsal motor nucleus of the vagus, the hypoglossal nucleus, the inferior olivary nucleus, and lobes 9 and 10 of the vermis cerebelli of adult SHR when compared with adult WKY. Our results support the hypothesis of a role for brain substance P in blood pressure regulation and in genetic hypertension in rats.

High concentration of atrial natriuretic peptide (99-126) (ANP) receptors were localized by quantitative autoradiography in superior cervical and stellate ganglia from young and adult Wistar Kyoto (WKY) rats. ANP increased cyclic GMP formation in stellate ganglia from adult rats. Both young and adult spontaneously hypertensive rats (SHR) had a much lower number of ANP receptors in the sympathetic ganglia. In spite of low receptor concentration, the cyclic GMP response to ANP in SHR was unchanged. These results suggest the existence of physiologically active ANP receptors in the rat sympathetic ganglia. These receptors may also be involved in the pathophysiology of spontaneous hypertension.

Angiotensin II has been implicated in the regulation of adrenocorticotropin and vasopressin secretion. Angiotensin II may influence the secretion of these hormones either directly at the pituitary gland or by increasing corticotropin-releasing hormone or vasopressin release from cells that are located in the paraventricular hypothalamic nucleus. Pituitary hormone release may also be influenced by circulating angiotensin II through receptors outside the blood-brain barrier in the subfornical organ. We have used alterations in angiotensin II receptors in hypophysectomized, adrenalectomized, and vasopressin-deficient Brattleboro rats as indicators of the activity of angiotensin II in the regulation of adrenocorticotropin and vasopressin secretion. Angiotensin receptor number in the paraventricular nucleus and the subfornical organ, but not in the anterior pituitary gland, was significantly decreased by adrenalectomy, and this effect was reversed by corticoids. Vasopressin deficiency decreased angiotensin receptors in the subfornical organ and increased them in the anterior pituitary gland but did not affect angiotensin II binding in either magnocellular or parvocellular subnucleus of the paraventricular nucleus. Our results suggest that angiotensin II may have a corticoid-dependent role in the regulation of corticotropin-releasing hormone secretion, which could be important in the adaptation to elevated corticosterone secretion in stress.

Angiotensin II (ANG) binding sites were quantified in single pituitary glands from 4-week-old and 14-week-old male spontaneously hypertensive rats (SHR) and age-matched male normotensive Wistar-Kyoto (WKY) control rats after incubation with 125I-[Sar1]-ANG, autoradiography with computerized densitometry, and comparison to 125I-standards. The maximum binding capacity (Bmax) decreased while the dissociation constant (Kd) for ANG increased in 14-week-old SHR when compared to age-matched WKY control rats (Bmax: 265 +/- 9 and 224 +/- 4 fmol/mg protein; Kd: 0.79 +/- 0.04 and 1.14 +/- 0.08 10(-9) M in WKY and SHR, respectively). Conversely, no difference between rat strains was found in 4-week-old animals. Our results suggest that pituitary ANG binding sites may play a role in the pathophysiology of established genetic hypertension.

Angiotensin II binding sites were localized and quantified in rat stellate and superior cervical ganglia by quantitative autoradiography using 125I-Sar1-angiotensin II as a ligand. Both ganglia possess a single class of angiotensin II binding sites. High concentrations of binding sites were localized in the areas rich in principal ganglion cells. These binding sites might mediate the facilitatory action of angiotensin II on the ganglionic transmission.

© The Author 2014. Published by Oxford University Press. All rights reserved., Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-β (Aβ) peptide. We recently showed that Aβ leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Aβ impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions., This work was supported by Fundação para a Ciência e a Tecnologia (FCT) Grants SFRH/BD/62828/2009 (to A.J.S.) and SFRH/BPD/81627/2011 (to S.H.V.), EU (COST B-30 concerted action), Gabinete de Apoio à Investigação Científica, Tecnológica e Inovação (GAPIC)—15th Programme for Education and Science (to S.P and S.L), and Bayer grant (to A.P.C). D.B. and V.B.S. are supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease), Inserm, CNRS, DN2M, FEDER, France Alzheimer, Région Nord/Pas-de-Calais, LECMA, ANR (ADORATAU), and FUI MEDIALZ. E.C are supported by ERC AdG 322742-iPlasticity, Academy of Finland CoE Program and Sigrid Jusus foundation.

We have studied the properties of angiotensin II binding sites in the paraventricular nucleus, subfornical organ and anterior pituitary lobe of rats subjected to repeated immobilization stress. This treatment produced significant increase in the density of angiotensin I I binding sites in these two nuclei without any significant alteration in binding affinity. Repeated stress did not alter angiotensin II binding properties in the anterior pituitary lobe. Our results suggest that brain angiotensin binding sites may have a role in regulation of the stress response.

We used quantitative in vitro autoradiography to localize and characterize 2-125I-melatonin binding sites in the rat suprachiasmatic nuclei in relation to pineal melatonin production. In a light:dark cycle of 12:12 h, binding density exhibited significant diurnal variation with a peak at the dark-light transition and a trough 12 hours later. Saturation studies suggested that the decreased binding at light-dark transition might be due to a shift of the putative melatonin receptor to a low affinity state.

The active uptake of 5-hydroxytryptamine (5-HT) was studied in vitro in the blood platelets of twelve pregnant women during their final two months of pregnancy. The control group consisted of twelve women who were, on average, four days post partum. No significant difference in the uptake of 5-HT by blood platelets was found between these groups. Thus, the rapid fall in blood estrogen and progesterone concentrations after parturition did not seem to influence the uptake of 5-HT in human blood platelets.

Specific binding sites for angiotensin II (Ang II) were localized in the red pulp of the spleen of rats and mice by quantitative autoradiography using 125I-Sar1-Ang II as a ligand. In the rat, the binding was saturable and specific, and the rank order for Ang II derivatives as competitors of 125I-Sar1-Ang II binding correlates well with their affinity for Ang II receptors in other tissues. Kinetic analysis in the rat spleen revealed a single class of binding sites with a KD of 1.11 nM and a Bmax value of 81.6 fmol/mg protein. Ang II binding sites were also localized on isolated rat spleen cells with similar affinity but with much lower Bmax, 9.75 fmol/mg protein. Ang II receptors were not detected in thymus sections from rats or mice, or on isolated rat thymocytes. The binding sites described here might represent a functional Ang II receptor with a role in the regulation of splenic volume and blood flow and in the modulation of the lymphocyte function.

Spontaneously hypertensive rats (SHR) have a much lower number of atrial natriuretic peptide (ANP) receptors in thymus and spleen from young and adult animals than age-matched normotensive controls. In spite of this low receptor concentration, the ANP-stimulated cyclic GMP response in isolated thymocytes and spleen cells from SHR was similar to that of normotensive control rats. Alterations in ANP receptor concentration in thymus and spleen of SHR may be related to the immune abnormalities described in these animals, and to the pathophysiology of genetic hypertension.

Quantitative autoradiographic methods were utilized to characterize specific, high-affinity vasoactive intestinal peptide binding sites (Kd = 310 +/- 60 pmol/L; Bmax = 93 +/- 11 fmol/mg protein) in frozen sections obtained from a mononuclear cell pellet derived from 20 ml of human blood. The method is at least one order of magnitude more sensitive than conventional membrane binding techniques, and it has the potential for wide applications in studies of neuropeptide, biogenic amine, and drug binding in clinical samples.

Publisher Summary The quantitative autoradiography determines that specific alterations in brain ANG II and ANP receptors occur when blood pressure or fluid consumption are modified and at least some of these central alterations are directly or indirectly related to changes in the peripheral peptide systems. The results indicate a role for the central ANG II and ANP systems in fluid and cardiovascular control and suggest that peripheral and central peptidergic systems are associated, perhaps through peptidergic receptors located outside the blood-brain barrier in contact with the general circulation. The circumventricular organs are connected to some other brain areas that belong to the endogenous brain ANG II and ANP systems. The ANG II and ANP receptor distributions overlap in many areas related to cardiovascular and fluid regulation as well as to the central control of sympathetic activity and pituitary function. Changes in peripheral peptide systems influence the brain directly through their circumventricular organ receptors and influence the central peptide systems as well. Brain receptor numbers can be modulated by alterations in peripheral peptide metabolism. The alterations in brain ANG II receptors during stress provide the first concrete evidence for a role of the peptide in the central control of the pituitary-adrenal axis.

DNA microarray technologies together with rapidly increasing genomic sequence information is leading to an explosion in available gene expression data. Currently there is a great need for efficient methods to analyze and visualize these massive data sets. A self-organizing map (SOM) is an unsupervised neural network learning algorithm which has been successfully used for the analysis and organization of large data files. We have here applied the SOM algorithm to analyze published data of yeast gene expression and show that SOM is an excellent tool for the analysis and visualization of gene expression profiles.

Neurotrophins are important regulators of neuronal plasticity in the developing and adult brain. In particular, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are implicated in these functions. The synthesis and release of BDNF is regulated by neuronal activity, and synaptic reorganization mediated by BDNF is thought to be a critical process which shapes neuronal networks to code optimally for environmentally relevant information. Recent evidence links neuronal plasticity and neurotrophin signalling in mood disorders. A polymorphism in the BDNF gene has been associated with depression and bipolar disorder. BDNF levels are reduced in postmortem brain samples and in the blood of depressed patients, and these reductions are reversible by successful antidepressant treatment. Furthermore, BDNF signalling plays a critical role in the mechanism of antidepressant drug action; at least in rodents, BDNF signalling appears to be both necessary and sufficient for the behavioural effects produced by antidepressant drugs. These data suggest that neurotrophin-mediated neuronal plasticity is a critical factor in mood disorders and in their therapy. Antidepressant treatments may, through enhanced BDNF signalling, improve the ability of critical brain circuits to respond optimally to environmental demands, a process that may be critical in the recovery from depression.

Neurotrophins affect neuronal development and plasticity via spatially localized effects, yet little is known about the subcellular distribution of the Trk neurotrophin receptors and the impact of this distribution on neurotrophin action. To address this, we examined the subcellular location of full-length TrkB and TrkC tyrosine kinase receptors and truncated TrkB isoforms after transfection of Madin–Darby canine kidney (MDCK) cells, dissociated primary hippocampal neurons, and cortical neurons within intact brain slices. Myc-, herpes virus glycoprotein (HVG)-, or FLAG-derived epitope–tagged receptor isoforms were created to allow their unambiguous identification and localization after transfection. All tagged receptors were appropriately synthesized, and full-length myc-TrkB and myc-TrkC mediated appropriate neurotrophin-signaling events. We found that full-length TrkB receptors were excluded from the apical domain of MDCK cells but that TrkC receptors were present in both apical and basolateral domains. Full-length TrkB and TrkC were found throughout transfected primary cultured hippocampal neurons and transfected neurons in neocortical brain slices and showed no evidence of vectorial sorting. Truncated forms of TrkB were also homogeneously distributed in MDCK cells, dissociated hippocampal neurons, and cortical neurons within slice preparations. Levels of full-length and truncated TrkB were examined in postsynaptic densities; both receptor isoforms were present but only moderately enriched in these structures. Together, these findings suggest that Trk receptors are uniformly distributed in both axonal and dendritic compartments and that local neurotrophin responses are controlled by other mechanisms.

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.

We studied the effects of selective chronic sodium or chloride depletion (0.005% in diet) on central and peripheral angiotensin II receptors in young rats. Chloride depletion produced the most significant increase in plasma renin activity and extracellular fluid volume contraction. In the brain, subfornical organ angiotensin II receptor concentration was decreased by sodium depletion and increased by chloride depletion. There were no significant changes in angiotensin II binding in the paraventricular nucleus. When sodium-depleted rats were water deprived for 3 days, subfornical organ angiotensin II receptor concentration increased, showing that normal sodium intake was not essential for increased numbers of angiotensin II receptors during dehydration. In the adrenal gland, chloride depletion decreased angiotensin II receptors in the medulla and zona glomerulosa. Conversely, sodium depletion increased angiotensin II receptors in the zona glomerulosa. In the kidney glomeruli and medulla, angiotensin II receptors were decreased by either sodium or chloride depletion. These results suggest different roles for sodium and chloride in the regulation of the peripheral and central renin-angiotensin system in young rats.

Fibroblast growth factor-5 (FGF-5) is a member of the fibroblast growth factor gene family, which has a signal sequence characteristic of secretory proteins. FGF-5 mRNA has previously been shown to be present in the adult mouse brain. Here we demonstrate that recombinant FGF-5 has neurotrophic activity on cultured rat septal cholinergic and raphe serotonergic neurons. The effect of FGF-5 on serotonin uptake was stronger than that evoked with either brain-derived neurotrophic factor or neurotrophin-3. FGF-5 also increased the choline acetyltransferase activity of cultured rat septal cholinergic neurons, the effect being additive to that of nerve growth factor. In situ hybridization experiments and immunohistochemistry using a specific anti-FGF-5 antibody demonstrated that FGF-5 is expressed in rat hippocampal neurons. Like nerve growth factor mRNA, the levels of FGF-5 mRNA in the rat hippocampus increased substantially during early postnatal development. In addition, injection of the muscarinic receptor agonist pilocarpine elevated FGF-5 mRNA. The presence of the secretory FGF-5 in the rat hippocampus, a target field of septal cholinergic and raphe serotonergic neurons, suggests that FGF-5 acts as a trophic factor for these neurons also in vivo.

Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)(−)) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)(−) mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor mediates fast excitatory neurotransmission, and agents that attenuate this function are neuroprotective, anesthetic, and psychotropic. To determine whether cAMP regulatable transcription factors play a role in the neurochemical actions of agents acting through NMDA receptors, the effects of the acute administration of uncompetitive and competitive antagonists on the expression of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) transcription factors were examined. In situ hybridization to rat brain sections revealed that ICER mRNA expression was significantly increased by uncompetitive NMDA receptor antagonists (MK-801, phencyclidine, ketamine, memantine) but not by the competitive antagonist CPP [(+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid] or other psychotropic agents (clozapine, haloperidol, desipramine). Major brain regions where ICER transcripts were increased were the hippocampus, parietal cortex layers IV and VI, temporal cortex, cingulate cortex, thalamus, and granule cell layer of the olfactory bulb. Northern and Western blot analyses indicated that CREM mRNA and protein, respectively, were also increased after MK-801 treatment, but ICER isoforms predominate during both basal and induced conditions. MK-801 also transiently increased the binding of proteins to cAMP response element, which was supershifted by anti-CREM antibody, indicating that increased mRNA and protein levels have functional consequences on gene transcription. These results provide evidence for the involvement of CREM and ICER family transcription factors in the pharmacologic effects of uncompetitive NMDA receptor antagonists.

In previous experiments it has been demonstrated that the synthesis of BDNF (brain-derived neurotrophic factor) and NGF in neurons of the hippocampus is regulated by neuronal activity. The glutamate system is predominantly responsible for upregulation and the GABAergic system for downregulation both in vitro and in vivo (Zafra et al., 1990, 1991). The aim of the present study is to examine the extent to which the cholinergic system is also involved in the regulation of NGF and BDNF mRNA and whether the regulatory contribution of the cholinergic system changes during development. Partial transection of the fimbria fornix bundle in the second postnatal week resulted in a reduction of BDNF and NGF mRNA levels in the hippocampus, suggesting that septal cholinergic input is involved in the regulation of hippocampal BDNF and NGF mRNA levels. Because the fimbria fornix bundle also contains fibers other than cholinergic ones, we further evaluated the importance of the cholinergic influence by injecting pilocarpine, a muscarinic agonist. Pilocarpine markedly increased hippocampal BDNF and NGF mRNA levels in both early postnatal and adult rats. In situ hybridization experiments demonstrated that pilocarpine led to an increase in BDNF expression in the CA1-CA4 regions of the hippocampus and in the dentate gyrus. However, pilocarpine increased NGF mRNA only in those neurons of the dentate gyrus and CA1-CA4 regions that also expressed NGF mRNA in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Trophic effects of the neuroprotective agent selegiline on cultured dopaminergic neurons were investigated and compared with the effects produced by brain derived neurotrophic factor (BDNF). Both treatments increased the total length of TH-positive neurites, but selegiline increased the average length of neuritic branches, whereas BDNF increased the formation of new branches. This trophic effect of selegiline may contribute to its action in neurodegenerative disease treatment.

Publisher Summary Neurotrophic molecules — in particular, the members of the nerve growth factor (NGF) gene family — have so far predominantly been considered under the aspect of their function in regulating neuronal survival and differentiation of specific populations of neurons during embryonic development and in maintaining characteristic structural and functional properties of these neurons in adulthood. Apart from the trophic support of specific populations of neurons during embryonic development and in adulthood, there is increasing evidence that neurotrophins also play a role in synaptic plasticity. This can be deduced from the following observations — (1) the regionally differential rapid regulation of synthesis of NGF and brain-derived neurotrophic factor (BDNF) by neuronal activity in response to subtle physiological stimuli; (2) the activity-dependent release of neurotrophins from all neuronal processes demonstrated so far only for NGF. This, together with the enhancement of transmitter release by neurotrophins from nerve terminals, expressing the corresponding Trk receptors, is compatible with the hypothesis that the neurotrophins may stabilize and/or rearrange specific synapses in an activity-dependent manner. This interpretation is also supported by recent observations that long-term potentiation is strongly impaired in hippocampal slices of homo- and heterozygote BDNF knock-out mice.

The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use increase the synthesis, release, or signaling of neurotrophins. Antidepressant drugs increase the synthesis and signaling of brain-derived neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and necessary for the antidepressant-induced behavioral effects. Furthermore, neurotrophins and other neurotrophic factors play a role in the acute and chronic responses produced by addictive drugs. Moreover, several neuroprotective drugs influence neurotrophin synthesis or signaling, although the significance of these effects is still unclear. These findings reveal a wider role for neurotrophic factors in drug action than has previously been expected, and they suggest that neurotrophin-induced trophic responses in neuronal connectivity and plasticity may be involved in the mechanism of action of several classes of CNS drugs. Improved assay systems are needed for the systematic screening of the effects of putative neuroprotective drugs on the synthesis, release, and signaling of neurotrophic factors, and for the evaluation of the functional role of these factors in the action of novel drug candidates.

Kommentti

We have investigated the expression of the mRNAs for brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in the hippocampus before and after induction of long term potentiation (LTP) of synaptic transmission in the dentate gyrus through stimulation of the perforant path (PP). A unilateral PP stimulation produced a bilateral increase in the mRNA for both BDNF and NGF in granular neurones of the dentate gyrus but not in other neurones in the hippocampus. The mRNA for neurotrophin-3 (NT-3) was bilaterally decreased by LTP but that of NT-4 remained at the basal level. These results suggest that individual neurotrophic factors may play different roles in neuronal plasticity.