bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of steroidal levels by adrenalectomy/castration and inhibition of neurosteroid synthesis enzymes affect σ1 receptor‐mediated behaviour in mice
Authors: Phan Vân‐Ly , Su Tsung‐Ping , Privat Alain , Maurice Tangui 
Published: March 2003

AbstractThe interaction between neurosteroids and sigma1 (σ1) receptors may be of therapeutic interest during physiological or pathological ageing, particularly concerning their neuromodulatory role on cognitive functions. Neurosteroids modulate memory processes through a mechanism involving interactions with GABAA, N‐methyl‐
d‐aspartate and/or σ1 receptors. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of σ1 agonists, we investigated the effects of inhibitors of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. Trilostane, a 3β‐hydroxysteroid‐deshydrogenase inhibitor, blocks the pregnenolone to progesterone conversion and leads to a decrease of progesterone. Finasteride, a 5α‐reductase inhibitor, blocks the progesterone to 5α‐pregnane‐3,20‐dione conversion and leads to an accumulation of progesterone. The in vivo binding of (+)‐[3H]SKF‐10 047 to σ1 sites was measured in the mouse hippocampus and cortex. The attenuating effect of the selective σ1 agonist PRE‐084 (0.1–3 mg/kg) against dizocilpine (0.15 mg/kg)‐induced learning impairment was examined using spontaneous alternation behaviour, step‐down passive avoidance and place learning in the elevated plus‐maze. The in vivo (+)‐[3H]SKF‐10 047 binding appeared significantly increased in AdX/CX mice and after trilostane treatment (10 mg/kg twice a day, 7 days), compared with sham‐operated animals. The finasteride treatment (25 mg/kg, 7 days) significantly decreased binding levels. The learning deficits induced by dizocilpine were not affected by the treatments. The antiamnesic effect of PRE‐084 was facilitated in AdX/CX mice and even more after trilostane treatment, as several parameters for animals treated with both PRE‐084 and dizocilpine returned to control values. The PRE‐084 effect was blocked after finasteride. These results confirmed that endogenous neurosteroidal levels modulate σ1 receptor‐mediated behaviour directly, and revealed that, among neurosteroids, progesterone may be the main modulator of σ1 receptors.
Li+ and muscarine cooperatively enhance the cationic tail current in rat cortical pyramidal cells
Authors: Okada Takashi , Kang Youngnam , Ohmori Harunori 
Published: March 2003

AbstractLi+ is known to facilitate the onset of status epilepticus induced by cholinergic stimulation, although the underlying mechanisms are not clear. Under whole‐cell current clamp conditions with a CsCl‐based internal solution, cortical pyramidal cells display a single plateau‐spike followed by a slow depolarizing afterpotential (DAP) in response to injection of a short current pulse. However, the same current pulse generated a burst of plateau‐spikes after application of Li+ (2 m
m) and muscarine (10 μm). As similar bursts of plateau‐spikes were generated through an enhancement of the slow DAP when [K + ]o was raised (
Kang et al. 1998
), we have investigated the effects of Li+ and muscarine on the Ca2+‐dependent cationic current underlying the slow DAP, measured as the slow tail current evoked after the offset of depolarizing voltage pulses. Muscarine enhanced the amplitudes of both early and late components of the slow tail current. This effect of muscarine was markedly potentiated by Li+, while Li+ by itself affected the slow tail current only slightly. Intracellular application of heparin (0.5–1 mg/mL) suppressed the effect of muscarine in the presence of Li+. These results suggest that inositol‐trisphosphate‐induced Ca2+ release is involved in the cooperative enhancement of the slow tail current, and this cooperation may be one of the mechanisms underlying facilitation of the onset of epilepsy induced by these agents.
Neuroprotection of cultured foetal rat hippocampal cells against glucose deprivation: are GABAergic neurons less vulnerable or more sensitive to TCP protection?
Authors: Chaudieu Isabelle , Privat Alain 
Published: March 2003

AbstractIn the rat brain, hippocampal neurons are particularly sensitive to secondary excitotoxic injury induced by ischaemia or hypoglycaemia. To determine some distinctive features of vulnerability among neuronal phenotypes in the hippocampus following a metabolic insult, we used an in vitro model of mild glucose deprivation. Primary cultures from the rat hippocampus (21 days in vitro) were deprived of glucose for 4 h and then were returned to the standard medium for 24 or 48 h. Survival of the GABAergic neuronal population was evaluated both by measuring [3H]GABA uptake and by counting GAD65‐immunostained cells. This was compared with the survival of the total neuronal population evaluated by counting the neurofilament‐200‐immunostained cells. Glucose deprivation for 4 h followed by a recovery period of 48 h induced a decrease of 59% and 40% in the number of GAD65‐ and neurofilament‐200‐immunostained cells, respectively. Thus, GABAergic neurons were slightly more vulnerable to glucose deprivation than the other neurons in the hippocampal cell cultures. When the excitotoxic component of cellular death was blocked in the presence of TCP, an NMDA‐antagonist, the survival of GABAergic neurons was almost complete after 48 h of recovery. In contrast, measurements of the release of lactate dehydrogenase in the medium indicated that TCP largely protected hippocampal cells after 24 h but was ineffective after 48 h. This observation was confirmed by immunostaining data which showed that after 48 h TCP did not significantly increase the survival of neurofilament‐200‐immunostained cells. These results indicate that after glucose deprivation and a recovery period of 48 h, GABAergic neurons in hippocampal cell cultures are not more resistant than other neurons but they are more sensitive to TCP protection.
Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA‐1)
Authors: Bretschneider Frank , Wrisch Anja , Lehmann‐Horn Frank , Grissmer Stephan 
Published: March 2003

AbstractEpisodic ataxia type 1 (EA‐1) is a rare neurological disorder and was the first ionic channel disease to be associated with defects in a potassium channel. Until now 10 different point mutations in the KCNA1‐gene have been reported to cause this disorder. We have investigated the functional consequences of two mutations leading to amino acid substitutions in the first and sixth transmembrane segments of a Kv1.1 channel subunit, by means of the patch‐clamp technique; we injected cRNA coding for, respectively, F184C and V408A mutant Kv1.1 channels into mammalian cells and compared the resulting currents with those in the wild‐type. The expression levels of F184C and V408A mutant channels relative to that of the wild‐type was 38 and 68%, respectively. Since the single‐channel conductance of the F184C mutant was similar to that of the wild‐type (12 pS) without an apparent change in the maximum open probability, we conclude that the lower expression level in the F184C mutant channels is due to a reduced number of functional channels on the cell surface. F184C activated slower, and at more depolarized potentials, and deactivated faster compared with the wild‐type. V408A channels deactivated and inactivated faster compared with the wild‐type. Studies with different extracellular cations and tetraethylammonium gave no indication that the pore structure was changed in the mutant channels. Acetazolamide, that is helpful in some patients suffering from EA‐1, was without effect on Kv1.1 wild‐type or mutant channels. This study confirms and extends earlier studies on the functional consequences of Kv1.1 mutations associated with EA‐1, in an attempt to understand the pathophysiology of the disease.
Can GABAA conductances explain the fast oscillation frequency of absence seizures in rodents?
Authors: Destexhe Alain 
Published: March 2003

AbstractRodent models of absence epilepsy generate spike‐and‐wave oscillations at relatively fast frequency (5–10 Hz) compared with humans (≈ 3 Hz). Possible mechanisms for these oscillations were investigated by computational models that included the complex intrinsic firing properties of thalamic and cortical neurons, as well as the multiple types of synaptic receptors mediating their interactions. The model indicates that oscillations with spike‐and‐wave field potentials can be generated by thalamocortical circuits. The frequency of these oscillations critically depended on GABAergic conductances in thalamic relay cells, ranging from 2–4 Hz for strong GABAB conductances to 5–10 Hz when GABAA conductances were dominant. This model therefore suggests that thalamocortical circuits can generate two types of spike‐and‐wave oscillations, whose frequency is determined by the receptor type mediating inhibition in thalamic relay cells. Experiments are proposed to test this mechanism.
Facilitation of GABA release by arachidonic acid in rat hippocampal synaptosomes
Authors: Cunha R. A. , Ribeiro J. A. 
Published: March 2003

AbstractArachidonic acid (AA) is proposed to be a facilitatory retrograde messenger in hippocampal glutamatergic synapses. In this study, we found that AA (10 μM) increased the basal outflow (19 ± 4%) and the K+‐evoked release of [3H]GABA (38 ± 3%) from rat hippocampal synaptosomes. This effect is likely to be a direct action of AA, as it was not mimicked by arachidic acid (10 μ M) and was not modified by inhibition of either lipooxygenase with nordihydroguaiaretic acid (50 μM) or cyclooxygenase with indomethacin (100 μM). Activation of protein kinase C may be involved, as chelerythrine (6 μM), a protein kinase C inhibitor, attenuated the AA (10 μM)‐facilitation of K+‐evoked [3H]GABA release by 58 ± 5%. Phospholipase A2 (2 U/mL), an enzyme that releases AA, and melittin (1 μM), a phospholipase A2 activator, mimicked the AA‐facilitation of evoked [3H]GABA release (70 ± 6% and 76 ± 7% facilitation, respectively). These results show that exogenously added and endogenously produced AA increased basal outflow and K+‐evoked release of [3H]GABA from rat hippocampal synaptosomes. Thus, AA can no longer be considered solely a facilitatory neuromodulator in the hippocampus, as this AA‐facilitation of the release of the main inhibitory neurotransmitter may predominate under certain circumstances.
The intrinsic specification of γ‐aminobutyric acid type A receptor α6 subunit gene expression in cerebellar granule cells
Authors: Bahn Sabine , Wisden William , Dunnett Stephen B. , Svendsen Clive 
Published: March 2003

AbstractThe patterns of γ‐aminobutyric acid type A (GABAA) receptor subunit gene expression in the brain are complex. For example, mouse hippocampal dentate granule cells express many subunit genes, whereas adult cerebellar granule cells, which may share differentiation mechanisms, have a smaller compliment and uniquely express the α6 subunit gene. To see how the α6 expression component arises, i.e. if intrinsically or environmentally specified, we used a mouse line (Δα6lacZ) with a β‐galactosidase reporter inserted into the α6 gene. Precursor cells from postnatal day 1 Δα6lacZ cerebellum were transplanted to the adult hippocampus and cerebellum of wild‐type mice; 4 weeks after transplantation, Δα6lacZ cells expressed α6‐lacZ in the hippocampus, amygdala and cerebellum. Thus, different adult environments support both the development and maintenance of α6 gene expression from cerebellar granule cell precursors. Establishing α6 gene expression is not likely to require specific patterns of neurotransmitter innervation or other factors present only in the developing brain; instead, α6 expression can be timed and maintained autonomously.
Selective expression of the NOS II isoform during mouse vestibulocochlear receptorgenesis
Authors: Arnhold S. , Klinz F. J. , Bloch W. , Hess A. , Andressen C. , Addicks K. 
Published: March 2003

AbstractBased on in vitro studies, nitric oxide (NO) is reported to be involved in initial neuronal differentiation. In order to compare this finding with the situation in vivo, we have looked for the expression of the three NO synthase isoforms in the developing mouse vestibulocochlear system. From these isoforms only the inducible NOS II is expressed during inner ear development. Examination of a series of embryonic and early postnatal animals, up to postnatal day 6, reveals a maturation‐dependent, monophasic expression of this isoform. Initial expression is observed by day 10 of gestation in nerve cells of the vestibolocochlear ganglion and on their fibres. By day 14 of gestation, these afferent fibres penetrate the epithelium of the prospective receptor fields making contact with early, differentiating immunoreactive cochlear hair cells and receptor cells of the macula and crista ampullaris. This receptor‐cell‐derived immunoreactivity vanished in differentiated sensory hair cells by postnatal day 6, when both the constitutive isoforms and subsequent activated members of the down stream second messenger cascade (guanylate cyclase/cGMP) of the adult mouse were not then detectable. The strict phasic expression of NOS‐II, independent of the second messenger system mentioned above, implies that there is a unique role for the inducible NOS isoform in nerve cell differentiation, independent of the NO/guanylate cyclase/cGMP pathway.
Calcium‐dependent inactivation of the monosynaptic NMDA EPSCs in rat hippocampal neurons in culture
Authors: Medina Igor , Leinekugel Xavier , Ben‐Ari Yehezkel 
Published: March 2003

AbstractThe effects of increased dendritic calcium concentration ([Ca2+]i) induced by single action potentials on monosynaptic glutamatergic excitatory postsynaptic currents (EPSCs) were studied in cultured rat hippocampal neurons. To investigate the respective roles of pre‐ and postsynaptic elements in the depolarization‐induced NMDAR inactivation, we have performed simultaneous paired whole‐cell recordings from monosynaptically connected pre‐ and postsynaptic hippocampal neurons. We report that the single firing of the postsynaptic neuron did not result in inactivation of the NMDAR‐EPSC, whereas a burst of depolarizing steps transiently depressed the NMDAR‐EPSCs in both pyramidal cells and interneurons. This effect was mediated by postsynaptic voltage‐gated Ca2+ influx, as it was prevented by: (i) buffering postsynaptic [Ca2+]i with 30 m
m BAPTA; (ii) removing extracellular Ca2+; or (iii) applying Cd2+o (100 μm), a voltage‐gated calcium channel blocker. It does not involve presynaptic mechanisms as it selectively affected NMDA but not α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptor‐mediated EPSCs. These results suggest that inactivation of NMDAR‐channels by voltage‐gated Ca influx is a general property of hippocampal neurons, which may play an important role in reducing postsynaptic NMDAR Ca2+ influx that leads to plasticity or excitotoxicity during sustained neuronal activity.
Behavioural conditions affecting saccadic eye movements elicited electrically from the frontal lobes of primates
Authors: Tehovnik Edward J. , Slocum Warren M. , Schiller Peter H. 
Published: March 2003

AbstractWe assessed the effects of varying the time at which electrical stimulation was delivered to the dorsomedial frontal cortex (DMFC) and the frontal eye fields (FEF) relative to the onset of a visual target. Monkeys were required to fixate the visual target to obtain a drop of apple juice as reward. We found that the probability of eliciting saccades increased with increases in the delay of electrical stimulation relative to target onset. Also, the current threshold to evoke saccades decreased as electrical stimulation was delivered later following target onset. There were major differences in the magnitude of this effect with stimulation of the DMFC versus the FEF. The current threshold to evoke saccades from the DMFC was 16 times greater when electrical stimulation was delivered 200 ms after target onset as compared to when it was delayed 200 ms after target offset. In contrast, the current threshold to evoke saccades from the FEFs was only three times greater when stimulation was delivered under similar conditions. These results suggest that the FEF are more closely connected with the saccade generator for the execution of saccadic eye movements than is the DMFC, even though both regions have direct projections to brainstem oculomotor centres.
Long‐term effects of methylprednisolone following transection of adult rat spinal cord
Authors: Oudega M. , Vargas C. G. , Weber A. B. , Kleitman N. , Bunge M. B. 
Published: March 2003

AbstractClinically, high‐dose treatment with the glucocorticosteroid, methylprednisolone (MP), within 8 h after spinal cord injury, has been shown to improve neurological recovery. The current standard of care is to administer MP as a bolus of 30 mg/kg followed by a 23‐h infusion of 5.4 mg/kg/h to spinal cord injured patients. To better understand the role of MP in neuroprotection, we have studied how MP administration affects macrophage accumulation, tissue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete transection of the eighth thoracic spinal cord in the adult rat. A 30 mg/kg dose of MP was administered intravenously at 5 min, and 2 and 4 h after injury. The number of ED1 (antibody against microglia/macrophages) ‐positive cells was quantified in a 500‐μm‐wide strip of tissue directly adjacent and parallel to the transection. At all time points, MP treatment led to a significant decrease in the number of ED1‐positive cells in both rostral and caudal stumps. Over the 2‐month post‐transection period, the average MP‐induced reduction in the number of ED1‐positive cells was 82% in the rostral cord stump and 66% in the caudal stump. Using a computerized image analysis system, it was observed that MP treatment resulted in a significant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post‐injury. Over the 2‐month post‐lesion period, the average MP‐induced reduction in tissue loss in the caudal cord stump was higher than that in the rostral stump; 48 versus 37%, respectively. Immunostaining for neurofilaments and growth‐associated protein‐43 (GAP‐43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran amine showed that, in MP‐treated animals, dieback of vestibulospinal fibres, but not of corticospinal fibres, was significantly diminished at all time points studied. In addition, with MP administration, 1 and 2 weeks after injury, an increase in the number of vestibulospinal fibres was found at 1 and 2 mm from the transection, suggesting transient regenerative sprouting of these fibres. The results demonstrate that treatment with MP shortly after spinal cord transection in the adult rat led to a long‐term reduction of ED1‐positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesion at 1 and 2 weeks post‐lesion. The possible relationships between the inflammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.
Differential regulation of distinct phenotypic features of serotonergic neurons by bone morphogenetic proteins
Authors: Galter Dagmar , Böttner Martina , Krieglstein Kerstin , Schömig Edgar , Unsicker Klaus 
Published: March 2003

AbstractBone morphogenetic proteins (BMPs), growth and differentiation factor 5 (GDF5) and glial cell line‐derived neurotrophic factor (GDNF) are members of the transforming growth factor‐β superfamily that have been implicated in tissue growth and differentiation. Several BMPs are expressed in embryonic and adult brain. We show now that BMP‐2, –6 and –7 and GDF5 are expressed in the embryonic rat hindbrain raphe. To start to define roles for BMPs in the regulation of serotonergic (5‐HT) neuron development, we have generated serum‐free cultures of 5‐HT neurons isolated from the embryonic (E14) rat raphe. Addition of saturating concentrations (10 ng/mL) of BMP‐6 and GDF5 augmented numbers of tryptophan hydroxylase (TpOH) ‐immunoreactive neurons and cells specifically taking up 5,7‐dihydroxytryptamine (5,7‐DHT) by about two‐fold. Alterations in 5‐HT neuron numbers were due to the induction of serotonergic markers rather than increased survival, as shown by the efficacy of short‐term treatments. Importantly, BMP‐7 selectively induced 5,7‐DHT uptake without affecting TpOH immunoreactivity. BMP‐6 and –7 also promoted DNA synthesis and increased numbers of cells immunoreactive for vimentin and glial fibrillary acidic protein (GFAP). Pharmacological suppression of cell proliferation or glial development abolished the induction of serotonergic markers by BMP‐6 and –7, suggesting that BMPs act indirectly by stimulating synthesis or release of glial‐derived serotonergic differentiation factors. Receptor bodies for the neurotrophin receptor trkB, but not trkC, abolished the BMP‐mediated effects on serotonergic development, suggesting that the glia‐derived factor is probably brain‐derived neurotrophic factor (BDNF) or neurotrophin‐4. In support of this notion, we detected increased levels of BDNF mRNA in BMP‐treated cultures. Together, these data suggest both distinct and overlapping roles of several BMPs in regulating 5‐HT neuron development.
Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats
Authors: Venero César , Borrell José 
Published: March 2003

AbstractGlucocorticoids can rapidly affect neuronal function and behaviour in mammals. Several studies have suggested the possible existence of rapid, non‐genomic effects of glucocorticoids in the hippocampus. To investigate whether glucocorticoids could affect neurotransmission in the hippocampus through rapid, non‐genomic mechanisms, we studied the effects of acute glucocorticoid administration on extracellular amino acid levels in the CA1 area of the hippocampus. By means of microdialysis on freely moving rats, we observed that an intraperitoneal injection of corticosterone (2.5 mg/kg) induced a rapid (within 15 min) and transient (returning to basal levels by 35–45 min) increase in extracellular aspartate and glutamate levels (∼ 155–160%), both in sham‐operated and adrenalectomized rats. These effects occurred in parallel with a rise in corticosterone concentration, also detected by microdialysis, in this hippocampal area. Intrahippocampal perfusion of corticosterone by retrodialysis also produced the same fast and reversible effects on excitatory amino acid (EAA) levels. Extracellular concentrations of taurine and γ‐aminobutyric acid (GABA) were unchanged after intrahippocampal glucocorticoid administration. This corticosterone‐mediated rise in EAA levels was not inhibited by the presence of specific antagonists for the two types of intracellular corticosteroid receptors, nor by a protein synthesis inhibitor, anisomycin. Perfusion of dexamethasone, a synthetic glucocorticoid, elicited a similar effect to that observed with corticosterone treatment in all studied cases. However, non‐glucocorticoid steroids did not affect amino acid transmission in this hippocampal area. These results indicate that glucocorticoids induce a rapid and transient increase in hippocampal EAA levels in vivo that might be exerted through a novel non‐genomic mechanism of action.