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PubMed2005

A novel role of circadian transcription factor DBP in hippocampal plasticity.

In neurons, a variety of extracellular stimuli are capable of inducing transcriptional events that underlie complex processes ranging from learning to disease. The mechanisms linking these long-lasting cellular modifications to behavior remain to be established. Here, we show by microarray analysis that hippocampal activation of glucagon-like peptide-1 receptor (GLP-1R), which is associated with improved learning and neuroprotection, results in suppression of the transcription factor DBP (albumin D-site-binding protein). Recombinant adeno-associated virus (rAAV) based gene expression of DBP in the hippocampus of adult rats caused upregulation of mRNAs encoding constituents of the molecular clock, and the DBP target gene, pyridoxal kinase. Behaviorally, DBP over expression inhibited spatial learning but not memory, and enhanced susceptibility to kainate-induced seizures. This phenotype was paralleled by the activation of MAP kinase in dendritic regions of hippocampal neurons in vivo. These data suggest that DBP may represent an important transcriptional link between GLP-1R activation and neuroplasticity in the hippocampus.

Animals↗
PubMed1996

Genetic dissection of structural and functional components of synaptic plasticity. II. Fasciclin II controls presynaptic structural plasticity.

Increased neuronal activity (eag Shaker mutants) and cAMP concentration (dunce mutants) lead to increased synaptic structure and function at the Drosophila neuromuscular junction. Here, we show that the increase in synaptic growth is accompanied by an approximately 50% decrease in synaptic levels of the cell adhesion molecule Fasciclin II (Fas II). This decrease in Fas II is both necessary and sufficient for presynaptic sprouting; FasII mutants that decrease Fas II levels by approximately 50% lead to sprouting similar to eag Shaker and dunce, while transgenes that maintain synaptic Fas II levels suppress sprouting in eag Shaker and dunce. However, FasII mutants that cause a 50% increase in bouton number do not alter synaptic strength; rather, evoked release from single boutons has a reduced quantal content, suggesting that the wild-type amount of release machinery is distributed throughout more boutons.

Animals↗
PubMed1998

The messenger RNAs for both glial cell line-derived neurotrophic factor receptors, c-ret and GDNFRalpha, are induced in the rat brain in response to kainate-induced excitation.

Glial cell line-derived neurotrophic factor (GDNF) has two receptors, receptor-tyrosine kinase c-ret and glycosylphosphatidylinositol-linked cell surface receptor GDNFRalpha. Kainate-induced seizures, a widely studied model of neuronal plasticity and human epilepsy, have been shown to increase gene expression of several trophic factors, including GDNF, in the rat hippocampus. Here we show that systemic kainate-induced excitation leads to a transient increase of both c-ret and GDNFRalpha messenger RNAs in the rat brain. Northern analysis demonstrated that, in the hippocampus, the maximal 2.5-fold increase of c-ret and four-fold increase of GDNFRalpha messenger RNAs was observed after 12 h of kainate injection, in contrast to GDNF messenger RNA, which reaches its maximum in 4-6 h. The blocking of de novo protein synthesis by cycloheximide inhibited the induction of GDNF receptors by kainate, whereas blocking of the N-methyl-D-aspartate-type glutamate receptors by the antagonist dizocilpine maleate did not significantly alter the response. Thus, GDNF receptor messenger RNA increase by kainate depends on protein synthesis, but is not mediated by the N-methyl-D-aspartate receptor. GDNFRalpha and c-ret show distinct, but partially overlapping, patterns of expression in the brain after kainate treatment. GDNFRalpha messenger RNA was prominently induced in the dentate gyrus of the rat hippocampus, less in the habenular and reticular thalamic nuclei and cerebral cortex as revealed by in situ hybridization. C-ret transcripts were induced in the hilus of the hippocampus, several thalamic and amygdala nuclei and in superficial layers of the piriform cortex. These data suggest that GDNF and its receptors may play a local role in neuronal plasticity and in neuronal protection following epileptic insults.

Animals↗
PubMed2005

Differences in the regenerative response of neuronal cell populations and indications for plasticity in intraspinal neurons after spinal cord transection in adult zebrafish.

In zebrafish, the capacity to regenerate long axons varies among different populations of axotomized neurons after spinal cord transection. In specific brain nuclei, 84-92% of axotomized neurons upregulate expression of the growth-related genes GAP-43 and L1.1 and 32-51% of these neurons regrow their descending axons. In contrast, 16-31% of spinal neurons with axons ascending to the brainstem upregulate these genes and only 2-4% regrow their axons. Dorsal root ganglion (DRG) neurons were not observed to regrow their ascending axons or to increase expression of GAP-43 mRNA. Expression of L1.1 mRNA is high in unlesioned and axotomized DRG neurons. In the lesioned spinal cord, expression of growth-related molecules is increased in a substantial population of non-axotomized neurons, suggesting morphological plasticity in the spinal-intrinsic circuitry. We propose that locomotor recovery in spinal-transected adult zebrafish is influenced less by recovery of ascending pathways, but more by regrowth of descending tracts and rearrangement of intraspinal circuitry.

Animals↗
PubMed1993

Cycloheximide mimics effects of oestradiol that are linked to synaptic plasticity of hypothalamic neurons.

The synaptic connectivity of the rat arcuate nucleus, a hypothalamic area rich in oestradiol receptors, is rapidly affected by physiological modifications of hormonal levels. A rise of oestradiol in plasma elicits a coordinated neuronal-glial response that begins with a rapid fall in the number of small (< 10 nm) intramembrane particles and a rapid increase in the number of large (> 10 nm) intramembrane particles in neuronal membranes, followed by a modification in the branching of astrocytic processes and finally results in decreased number of axo-somatic synapses and increased glial wrapping of the neuronal somas. In the course of a series of studies aimed to test possible non-genomic effects of oestradiol on neuronal membranes we analyzed the effect of the systemic administration of the protein synthesis inhibitor cycloheximide on the ultrastructure of arcuate neurons and granule cells of the cerebellar cortex, an area of the brain with low levels of estrogen receptors. Cycloheximide resulted in a significant inhibition of protein synthesis in hypothalmus and cerebellum of ovariectomized rats. Under these circumstances, the number of small intramembrane particles was reduced in hypothalamic and cerebellar neuronal membranes while the number of large intramembrane particles showed a decrease in cerebellar membranes and a transient increase in arcuate neuronal somas. Furthermore, cycloheximide resulted in an increased glial wrapping of arcuate neuronal somas but not of cerebellar granule cells. The ensheathing of arcuate neurons by glial was associated with a 41% decrease in the number of axo-somatic synapses. These results indicate that the protein synthesis inhibitor cycloheximide may elicit the integrated neuronal-glial response that is associated with the hormonally induced remodelling of synaptic contacts on arcuate neurons.

Animals↗
PubMed1986

Osmotic stimulation causes structural plasticity of neurone-glia relationships of the oxytocin but not vasopressin secreting neurones in the hypothalamic supraoptic nucleus.

A comparative quantitative analysis was carried out on identified supraoptic neurones of male and female Wistar and Long Evans rats under normal conditions and after chronic osmotic stimulation, and in homozygous Brattleboro rats suffering from diabetes insipidus. The neurones were identified by immunocytochemical or morphological means. Osmotic stimulation resulted in significant increases in the number and extent of direct neuronal appositions and in the number of presynaptic terminals contacting two neurosecretory cells simultaneously ("double" synapses). In the supraoptic nuclei of both sexes these increases were restricted to the oxytocin secreting neurones. In Brattleboro homozygous rats treated with vasopressin, the proportion of oxytocinergic neurones in apposition was not modified, but the number of appositions per soma profile decreased as did the incidence of "double" synapses. In nuclei of osmotically stimulated rats, increase in cell volume affected both types of neurosecretory cell and was accompanied by an increase of the absolute extent of glial coverage. However, the extent of glial coverage of the oxytocinergic neurones did not match the hypertrophy of the cells, resulting in a decrease in their relative glial coverage, compared to normal hydrated animals. The increased neuronal appositions, therefore, cannot result simply from a retraction of glial processes. The structural reorganization of the oxytocinergic system observed during chronic osmotic stimulation was as extensive as that observed at lactation. Moreover, the changes were as extensive in Wistar as in Brattleboro lactating rats, although the latter have an added osmotic stimulus. This implies that lactation and osmotic stimulation do not produce additive effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Plasticity of catecholaminergic neurons in aged rat brain: reinnervation and functional recovery after axotomy.

Regenerative growth at the lesion site, reinnervation of a target nucleus and functional manifestations of recovery were studied in aged (20 and 30 months old) rats subjected to long-term transection of catecholaminergic (CA) fibers which contact and influence neurons of the supraoptic nucleus (SON). Small bilateral knife cuts were placed stereotaxically just caudal and medial to the SON. CA histofluorescence, induced by formaldehyde-glutaraldehyde (FAGLU) or aluminum-formaldehyde (ALFA) methods, was examined in hypothalamus at 2, 14, 21 and 60 days postsurgically. Water consumption, and urine volume and osmolality, were monitored presurgically, and through survival times. Subtotal CA denervation in the SON, and typical axonal transmitter "pile-up" at the lesion site, were evident two days after surgery. Among these degenerative profiles, which persisted for up to three weeks, fine-sized new fibers were apparent at the lesion, beginning between 2 and 14 days, and persisting throughout the period studied. At 21 days, and progressively thereafter, SON neurons were rimmed with fluorescent varicosites. Water consumption initially was depressed, but returned to presurgical mean levels by nine days. Urine volume returned to normal by 32 days. Urine osmolality showed a recovery by approximately three weeks. These functional parameters rebounded to levels higher than presurgical means among 20 month old, but not 30 month old, rats beyond 6 weeks survival, concurrent with a morphological hyperinnervation. The results reaffirm morphological regeneration, and support reinnervation and functional recovery, which extend considerably into the aging process.

Afferent Pathways↗
PubMed2004

Suppression subtractive hybridization and microarray identification of estrogen-regulated hypothalamic genes.

The gonadal steroid estrogen is a pleiotropic hormone that has multiple effects on numerous cellular functions. One of estrogen's major targets is the brain, where the steroid not only affects growth, differentiation, and survival of neurons, but also regulates cell excitability. Because estrogen modulates multiple, overlapping signaling pathways, it has been difficult to scrutinize the transcriptional activity of the steroid. Therefore, we still lack a global picture of how different genes interact and are regulated by estrogen. Herein we report the use of suppression subtractive hybridization followed by custom microarray analysis of thousands of genes that are differentially expressed during the negative feedback phase of the female reproductive cycle. We have found a number of key transcripts that are regulated by estrogen and contribute to the alteration in synaptic transmission and hence excitability of hypothalamic neurons (e.g., GABA neurons). These include gec-1, GABA(B)R2, PI3 kinase subunit p55gamma, and a number of proteins containing pleckstrin homology domains that are critical for plasma membrane targeting. Studies are underway to refine our analysis to individual nuclei and individual cells. However, what has emerged from this highly sensitive microarray analysis is that estrogen affects neuronal plasticity in hypothalamic neurons not only by transcription of new membrane proteins (e.g., receptors and channels), but also by altering expression of downstream signaling molecules and proteins involved in neurosecretory pathways.

Animals↗
PubMed2004

Olfactometric and rhinomanometric outcomes in post-menopausal women treated with hormone therapy: a prospective study.

BACKGROUND: The aim of this prospective study was to evaluate the effects of hormone therapy (HT) on olfactory sensitivity in post-menopausal women. METHODS: Forty-six naturally post-menopausal women underwent rhinomanometric and olfactometric measurements to compare nasal airflow resistance values and olfactometric thresholds during the eighth month of HT treatment with baseline levels prior to starting HT. Eighteen women used an oral HT regimen, and twenty-eight women used transdermal patch HT. RESULTS: Rhinomanometric values during HT were statistically differ from those at baseline (P < 0.001). Olfactometric threshold data indicated a higher sensitivity during the HT treatment than at baseline (P < 0.001). Finally, no statistically significant difference was observed among women using oral or patch HT administration on rhinomanometric and olfactometric values. CONCLUSIONS: Our study demonstrates that 8 months of treatment with estrogen and progestogens in HT preparations has an effect on nasal airflow resistance and the olfactory thresholds to odours. We believe that estrogens could influence neuronal plasticity, and the neuronal conduction time into the olfactory system. Our findings confirm that gonadal steroids such as estrogen have an influence on non-genital targets; this relationship might have a beneficial impact on sensorineural communication and emotional behaviour.

Administration, Oral↗
PubMed2000

Serum growth factors and neuroprotective surveillance: focus on IGF-1.

The adult brain requires a constant trophic input for appropriate function. Although the main source of trophic factors for mature neurons is considered to arise locally from glial cells and synaptic partners, recent evidence suggests that hormonal-like influences from distant sources may also be important. These include not only relatively well-characterized steroid hormones that cross the brain barriers, but also blood-borne protein growth factors able to cross the barriers and exert unexpected, albeit specific, trophic actions in diverse brain areas. Insulin-like growth factor I (IGF-I) is until now the serum neurotrophic factor whose actions on the adult brain are best-characterized. This is because IGF-I has been known for many years to be present in serum, whereas the presence in the circulation of other more classical neurotrophic factors has only recently been recognized. Thus, new evidence strongly suggests that IGF-I, and other blood-borne neurotrophic factors such as Fibroblast Growth Factor (FGF-2) or the neurotrophins, exert a tonic trophic input on brain cells, providing a mechanism for what we may refer to as neuroprotective surveillance. Protective surveillance includes "first-line" defense mechanisms ranging from blockade of neuronal death after a wide variety of cellular insults to upregulation of neurogenesis when defenses against neuronal death are overcome. Most importantly, surveillance should also encompass modulation of homeostatic mechanisms to prevent neuronal derangement. These will include modulation of basic cellular processes such as metabolic demands and maintainance of cell-membrane potential as well as more complex processes such as regulation of neuronal plasticity to keep neurons able to respond to constantly changing functional demands.

Animals↗
PubMed1999

[Synaptic structural organization as a determinant of selective sensitivity and plasticity of brain neurons in postanoxic period].

The neuro- and synaptoarchitectonics of the sensoty-motor cortex of the brain and cerebellum was comparatively analyzed in an experiment on adult albino rats. There was a relationship between the formation of axospinal synapses to the type of organization of paramembranous cytoskeleton. A role of cytoskeleton's factors of synaptic contacts in the pathogenesis of postanoxic selective neuronal lesion and in the compensatory reorganization of synaptoarchitectonics is hypothesized.

Animals↗
PubMed1996

Neuronal activity increases the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in rat hippocampus and cortex.

Activity-mediated gene expression is thought to play an important role in many forms of neuronal plasticities. We have used pentylenetetrazol-induced seizure that produces synchronous and sustained neuronal activity as a model to examine the mechanism(s) of gene activation. The transcription factor CREB (Ca2+/cAMP response element-binding protein) is thought to be necessary for long-term memory formation both in invertebrates and vertebrates. When phosphorylated on Ser133 either by cAMP-dependent protein kinase and/or Ca2+/calmodulin-dependent protein kinases, CREB increases transcription of genes containing the CRE (cAMP response element) sequence. Using an antibody that detects Ser133-phosphorylated CREB protein, we show that CREB phosphorylation is maximal between 3 and 8 min after the onset of seizure activity and declines slowly both in the hippocampus and the cortex. The total amount of CREB protein did not change at the time points examined. The increased phosphorylation of CREB protein is preceded by an increase in the amount of cAMP, suggestive of cAMP-dependent protein kinase activation, in the hippocampus and activation of Ca2+/calmodulin-dependent protein kinases in the cortex. Subsequent to CREB phosphorylation, the expression of the CRE-containing gene, c-fos, and the AP-1 complexes (heterodimers of Fos and Jun family members) is increased. These findings support the role of CREB-mediated gene expression in activity-dependent neuronal plasticities.

Animals↗
PubMed1991

Effects of competitive and noncompetitive NMDA receptor antagonists on kindling and LTP.

In the present study, comparative studies of the effects of competitive and noncompetitive antagonists of NMDA receptors (CPP, CGS19755 and MK-801) on two models of neuronal plasticity, kindling and long-term potentiation (LTP), were performed in rats. Systemic administration of CPP (5, 10 mg/kg), CGS19755 (5, 10 mg/kg) or MK-801 (1, 2 mg/kg) strongly retarded kindling development from the amygdala (AM), in which the early stage of kindled seizures and the growth of afterdischarges (ADs) recorded from the AM were significantly suppressed. After establishment of kindling, however, these compounds only reduced the previously AM-kindled seizure stage without shortening the AD duration. These NMDA receptor antagonists with the same dose sufficient for suppressing AM kindling almost completely blocked LTP of the synaptic component in the hippocampal dentate gyrus following high-frequency trains of the perforant path in urethane-anesthetized rats. These results further support the hypothesis that neuronal plasticity is induced by activation of the NMDA receptor complex and one of the basic neuronal mechanisms underlying kindling may be a long-lasting increase in synaptic transmission.

Animals↗
PubMed1998

Modulation of pre- and postsynaptic calcium dynamics by ionotropic glutamate receptors at a plastic synapse.

This study was conducted to assess the role of ionotropic glutamate receptors in the modulation of calcium dynamics on both sides of a vertebrate plastic synapse. Retrograde labeling of neuronal elements with high-affinity calcium-sensitive dyes was used in conjunction with confocal imaging techniques in an in vitro lamprey brain stem preparation. A prolonged calcium transient was measured both pre- and postsynaptically in response to a period of high-frequency ("tetanic") stimulation to the vestibulospinal-reticulospinal synapse. The ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and D,L-2-amino-5-phosphonopentanoate (D,L-AP5; 100 microM) reduced the calcium signal in both compartments of the synapse. The presynaptic D,L-AP5-sensitive component was enhanced markedly by the removal of Mg2+ from the superfusate. Increasing the extracellular stimulus intensity progressively augmented the presynaptic calcium signal, suggesting the recruitment of excitatory axo-axonic inputs onto these fibers. Further, the presence of an excitatory amino acid-mediated presynaptic potential underlying a component of the Ca2+ signal was demonstrated by electrophysiological recordings from vestibulospinal axons. Bath application of agonist, in the presence of tetrodotoxin (1 microM), confirmed the existence of N-methyl-D-aspartate receptors at the presynaptic element capable of modulating calcium levels. The postsynaptic Ca2+ response, which is known to be necessary for long-term potentiation (LTP) induction at this synapse, was localized to areas of the dendritic tree that correlated with the location of known synaptic inputs; thus the synaptically activated rise in postsynaptic calcium may confer the synapse specificity of LTP induction previously demonstrated. In summary, we have demonstrated the existence of physiologically activated presynaptic ionotropic glutamate receptors that are capable of modulating levels of intracellular calcium and have highlighted the importance of receptor-mediated increases in postsynaptic calcium for neuronal plasticity in the lamprey.

2-Amino-5-phosphonovalerate↗
PubMed2000

Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence.

The tolerance and dependence after chronic medication with morphine are thought to be representative models for studying the plasticity, including the remodeling of neuronal networks. To test the hypothesis that changes in neuronal plasticity observed in opioid tolerance or dependence are derived from increased activity of the anti-opioid nociceptin system, the effects of chronic treatments with morphine were examined using nociceptin receptor knock-out (NOR(-/-)) mice and a novel nonpeptidic NOR antagonist, J-113397, which shows a specific and potent NOR antagonist activity in in vitro [(35)S]GTPgammaS binding assay and in vivo peripheral nociception test. The NOR(-/-) mice showed marked resistance to morphine analgesic tolerance without affecting morphine analgesic potency in tail-pinch and tail-flick tests. The NOR(-/-) mice also showed marked attenuation of morphine-induced physical dependence, manifested as naloxone-precipitated withdrawal symptoms after repeated morphine treatments. Similar marked attenuation of morphine tolerance was also observed by single subcutaneous (10 mg/kg) or intrathecal (1 nmol) injection of J-113397, which had been given 60 min before the test in morphine-treated ddY mice. However, the intracerebroventricular injection (up to 3 nmol) did not affect the tolerance. On the other hand, morphine dependence was markedly attenuated by J-113397 that had been subcutaneously given 60 min before naloxone challenge. There was also observed a parallel enhancement of NOR gene expression only in the spinal cord during chronic morphine treatments. Together, these findings suggest that the spinal NOR system develops anti-opioid plasticity observed on morphine tolerance and dependence.

Animals↗
PubMed1997

Potassium currents in presynaptic hair cells of Hermissenda.

Apart from their primary function as balance sensors, Hermissenda hair cells are presynaptic neurons involved in the Ca(2+)-dependent neuronal plasticity in postsynaptic B photoreceptors that accompanies classical conditioning. With a view to beginning to understand presynaptic mechanisms of plasticity in the vestibulo-visual system, a locus for conditioning-induced neuronal plasticity, outward currents that may govern the excitability of hair cells were recorded by means of a whole-cell patch-clamp technique. Three K+ currents were characterized: a 4-aminopyridine-sensitive transient outward K+ current (IA), a tetraethyl ammonium-sensitive delayed rectifier K+ current (IK,V), and a Ca(2+)-activated K+ current (IK,Ca). IA activates and decays rapidly; the steady-state activation and inactivation curves of the current reveal a window current close to the apparent resting voltage of the hair cells, suggesting that the current is partially activated at rest. By modulating firing frequency and perhaps damping membrane oscillations, IA may regulate synaptic release at baseline. In contrast, IK,V and IK,Ca have slow onset and exhibit little or no inactivation. These two K+ currents may determine the duration of the repolarization phase of hair-cell action potentials and hence synaptic release via Ca2+ influx through voltage-gated Ca2+ channels. In addition, IK,Ca may be responsible for the afterhyperpolarization of hair cell membrane voltage following prolonged stimulation.

4-Aminopyridine↗