bluuebunny/crossref_metadata_2025_split huggingface dataset:
NMDA receptor subunits GluRε1, GluRε3 and GluRζ1 are enriched at the mossy fibre–granule cell synapse in the adult mouse cerebellum
Authors: Yamada Kazuyuki , Fukaya Masahiro , Shimizu Hidemi , Sakimura Kenji , Watanabe Masahiko 
Published: March 2003

AbstractCerebellar N‐methyl‐d‐aspartate (NMDA) receptors are concentrated in the granular layer and are involved in motor coordination and the induction of long‐term potentiation at mossy fibre–granule cell synapses. In the present study, we used immunohistochemistry to examine the distribution of NMDA receptor subunits in the adult mouse cerebellum. We found that appropriate pepsin pretreatment of sections greatly enhanced the sensitivity and specificity of immunohistochemical detection. As a result, intense immunolabelling for GluRε1 (NR2A), GluRε3 (NR2C), and GluRζ1 (NR1) all appeared in synaptic glomeruli of the granular layer. Double immunofluorescence showed that these subunits were colocalized in individual synaptic glomeruli. Within the glomerulus, NMDA receptor subunits were located between centrally‐located huge mossy fibre terminals and peripherally‐located tiny Golgi axon terminals. By immunoelectron microscopy, all three subunits were detected at the postsynaptic junction in granule cell dendrites, forming synapses with mossy fibre terminals. Consistent with the known functional localization, GluRε1, GluRε3, and GluRζ1 are, thus, anatomically concentrated at the mossy fibre–granule cell synapse. By contrast, immunohistochemical signals were very low in Purkinje cell somata and dendrites in the molecular layer. The lack of GluRζ1 immunolabelling in Purkinje cells was unexpected because the cells express GluRζ1 mRNA at high levels and high levels of GluRζ1 protein in the molecular layer were revealed by immunoblot. As Purkinje cells are exceptionally lacking GluRε expression, the discrepant result may provide in vivo evidence suggesting the importance of accompanying GluRε subunits in synaptic localization of GluRζ1.
Ceramide‐induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation
Authors: Willaime Sandrine , Vanhoutte Peter , Caboche Jocelyne , Lemaigre‐Dubreuil Yolande , Mariani Jean , Brugg Bernard 
Published: March 2003

AbstractCeramide, the central molecule of the sphingomyelin pathway, serves as a second messenger for cellular functions ranging from proliferation and differentiation to growth arrest and apoptosis. In this study we show that c2‐ceramide induces apoptosis in primary cortical neuron cultures and that this effect correlates with differential modulation of mitogen‐activated protein kinase (MAPK) cascades. Phosphorylation of extracellular signal‐regulated kinases (ERKs) and their upstream activators MAPK kinases (MEKs), as measured by immunoblotting is rapidly decreased by c2‐ceramide. However, the MEK inhibitor PD98059 alone does not induce apoptosis and in combination with c2‐ceramide it does not modify c2‐ceramide‐induced apoptosis. Treatment with c2‐ceramide increases p38 and c‐Jun N‐terminal kinase (JNK) phosphorylation before and during caspase‐3 activation. The p38 inhibitor SB203580 partially protects cortical neurons against c2‐ceramide‐induced apoptosis, implicating the p38 pathway in this process. The c2‐ceramide treatment also increases levels of c‐jun, c‐fos and p53 mRNA in primary cortical neuron cultures, but this is independent of p38 activation. Our study further elucidates the time‐courses of MAPK cascade modulation, and of c‐jun, c‐fos and p53 activation during c2‐ceramide‐induced neuronal apoptosis. It reveals that one of the activated kinases, p38, is necessary for this apoptosis.
ATP but not adenosine inhibits nonquantal acetylcholine release at the mouse neuromuscular junction
Authors: Galkin A. V. , Giniatullin R. A. , Mukhtarov M. R. , Švandová I. , Grishin S. N. , Vyskočil F. 
Published: March 2003

AbstractThe postsynaptic membrane of the neuromuscular synapse treated with antiacetylcholinesterase is depolarized due to nonquantal release of acetylcholine (ACh) from the motor nerve ending. This can be demonstrated by the hyperpolarization produced by the application of curare (H‐effect). ATP (1 × 10−5 m) decreased the magnitude of the H‐effect from 5 to 1.5 mV. The membrane input resistance and the ACh sensitivity were unchanged, and so changes in these cannot explain the ATP effect. Adenosine alone was without effect on the nonquantal release. On the other hand, both ATP and adenosine depressed the frequency of spontaneous miniature endplate potentials, to 56% and 43% respectively. The protein kinase A inhibitor Rp‐cAMP or the guanylyl cyclase inhibitor 1H‐[1,2,4]oxidiazolo[4,3‐a]quinoxalin‐1‐one did not affect the inhibitory influence of ATP on the H‐effect, whereas staurosporine, an inhibitor of protein kinase C, completely abolished the action of ATP. Suramin, an ATP antagonist, enhanced the H‐effect to 8.6 mV and, like staurosporine, prevented the inhibitory effect of ATP. ATP thus suppresses the nonquantal release via a direct action on presynaptic metabotropic P2 receptors coupled to protein kinase C, whilst adenosine exerts its action mainly by affecting the mechanisms underlying quantal release. These data, together with earlier evidence, show that nonquantal release of ACh can be modulated by several distinct regulatory pathways, in particular by endogenous substances which may or may not be present in the synaptic cleft at rest or during activity.
Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons
Authors: Szabo Steven T. , Blier Pierre 
Published: March 2003

AbstractReboxetine is a non‐tricyclic antidepressant with selective noradrenergic (NA) reuptake‐blocking effects. The effects of acute and sustained administration of reboxetine, on the firing activity of locus coeruleus NA neurons and dorsal raphe 5‐HT neurons, were assessed using in vivo extracellular unitary recording in rats anaesthetized with chloral hydrate. Reboxetine (0.1–1.25 mg/kg, i.v.) dose‐dependently decreased the firing activity of NA neurons (ED50 = 480 ± 14 µg/kg). A 2‐day treatment with reboxetine at 1.25, 2.5, 5, or 10 mg/kg per day (using osmotic minipumps implanted subcutaneously) produced significant decreases of 52%, 68%, 81%, and 83%, respectively, of NA firing activity. When the reboxetine treatment (2.5 mg/kg per day) duration was prolonged to 7 days, a 66% decrease in NA firing activity was observed which further decreased to 80% after 21 days of treatment. In contrast, 5‐HT neuron firing rate remained unaltered following short‐ and long‐term reboxetine treatments. The suppressant effect of the α2‐adrenoceptor agonist clonidine on the firing activity of NA neurons was unchanged in long‐term reboxetine‐treated rats, but its effect on the firing activity of 5‐HT neurons was blunted. The enhancement of NA firing activity by the 5‐HT1A agonist 8‐OH‐DPAT was abolished in long‐term reboxetine‐treated rats, whereas, the inhibitory effect of the 5‐HT2 agonist DOI was attenuated by about three‐fold. In conclusion, sustained NA reuptake blockade by reboxetine lead to profound alterations in the function of NA neurons and of 5‐HT receptors modulating their firing activity.
The group I metabotropic glutamate receptor antagonist S‐4‐CPG modulates the locomotor response produced by the activation of D1‐like, but not D2‐like, dopamine receptors in the rat nucleus accumbens
Authors: David Hélène N. , Abraini Jacques H. 
Published: March 2003

AbstractFunctional interactions between dopamine (DA) and glutamate neurotransmissions in both the dorsal and the ventral striatum have been described for long time. However, there is much controversy as to whether glutamate transmission stimulates or attenuates DA release and locomotor activity. We investigated the functional interactions on locomotor activity between group I metabotropic glutamatergic receptors (mGlu receptors) and both D1‐like and D2‐like DA receptors in the rat nucleus accumbens. Intra‐accumbens administration of the selective group I mGlu receptor antagonist S‐4‐CPG (0.2 or 2 µg per side), which had no effect when injected alone, prevented the increase in locomotor activity produced by the selective D1‐like receptor agonist SKF 38393 (1 µg per side). Co‐administration with S‐4‐CPG of the group I mGlu receptor agonist DHPG, but not of the group II mGlu receptor agonist APDC or the group III mGlu receptor agonist AP4, reversed the antagonistic effect of S‐4‐CPG on the SKF 38393‐induced increase in locomotor activity. This indicates that the antagonistic effect of S‐4‐CPG could result from an action at the group I mGlu receptors. In contrast, administration of S‐4‐CPG showed no effect on the locomotor responses produced by either the selective D2‐like receptor agonist LY 171555 (1 µg per side) or a mixed solution of SKF 38393 + LY 171555 (1 µg per side each). Altogether, these results confirm that glutamate transmission may control locomotor function through mGlu receptors in a DA‐dependent manner, and further indicate that group I mGlu receptors would interact with D1‐like receptors, but not D2‐like receptors, to modulate DA transmission and locomotor activity.
Sphingosine‐1‐phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades
Authors: Pébay Alice , Toutant Madeleine , Prémont Joël , Calvo Charles‐Félix , Venance Laurent , Cordier Jocelyne , Glowinski Jacques , Tencé Martine 
Published: March 2003

AbstractSphingosine‐1‐phosphate (S1P) is a potent lysophospholipid mediator mostly released by activated platelets. It is involved in several functions in peripheral tissues, but its effects in the central nervous system are poorly documented. Therefore, we have examined the effects of S1P on the proliferation of striatal astrocytes from the mouse embryo. These cells have been found to express mRNAs for the S1P receptors, Edg‐1 and Edg‐3. S1P stimulated thymidine incorporation and induced activation of extracellular signal‐regulated kinases (Erks). Both effects were prevented by U0126, an Erk kinase inhibitor. The S1P‐evoked activation of Erk1 was totally blocked in astrocytes pretreated with a combination of either phorbol ester (24 h) and LY294002, or phorbol ester (24 h) and pertussis toxin (PTX). Each individual treatment only partially inhibited Erk1 activation. This suggests that several separate mechanisms mediate this process, one involving protein kinase C and another involving Gi/Go proteins and phosphatidylinositol 3‐kinase. In contrast, the stimulatory effect of S1P on astrocyte proliferation was totally blocked by either PTX or LY294002, but not by a downregulation of protein kinase C. S1P dramatically inhibited the evoked production of cyclic AMP, a response that was impaired by PTX. Finally, S1P stimulated the production of inositol phosphates and increased intracellular calcium by mobilization from thapsigargin‐sensitive stores. These latter effects were mainly insensitive to PTX. Probably, Gi/Go protein activation and phosphoinositide hydrolysis are early events that regulate the activation of Erks by S1P. Altogether, these observations show that astrocytes are targets for S1P. Their proliferation in response to S1P could have physiopathological consequences at sites of brain lesions and alterations of the blood–brain barrier.
Colocalization of CGRP with 5‐HT1B/1D receptors and substance P in trigeminal ganglion neurons in rats
Authors: Ma Qing‐Ping , Hill Ray , Sirinathsinghji Dalip 
Published: March 2003

AbstractVasodilatation in the dura mater has been implicated in migraine pathogenesis. Anti‐migraine triptan drugs block vasodilatation by binding to 5‐HT1B/1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles. Previous studies suggest that calcitonin gene‐related peptide (CGRP) released from Aδ‐fibres plays a more important role than substance P (SP) released from C‐fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of triptan drugs is inhibiting CGRP release. In the present study, the relationship between CGRP and 5‐HT1B/1D receptors, and between CGRP and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining. CGRP, 5‐HT1B, 5‐HT1D and SP‐positive trigeminal ganglion neurons were all predominantly small and medium‐sized. In the trigeminal ganglia, ≈ 50% of CGRP‐positive neurons were 5‐HT1B positive. Similarly, ≈ 55% of CGRP‐positive neurons were 5‐HT1D immunoreactive. Approximately 50% of CGRP‐positive neurons were SP‐positive, while 93% of SP‐positive neurons were CGRP‐positive, suggesting that nearly all SP‐positive neurons also contain CGRP. The fibre types of the 5‐HT1B‐ and 5‐HT1D‐positive neurons were further investigated with an antibody against the A‐fibre marker 200‐kDa neurofilaments (NF200). Approximately 46% of the 5‐HT1B‐positive and 43% of the 5‐HT1D‐positive trigeminal ganglion neurons were also NF200 positive, indicating that many A‐fibre trigeminal neurons express 5‐HT1B or 5‐HT1D receptors. These results support the hypothesis that one important action of antimigraine drugs is the inhibition of CGRP release and that Aδ‐fibres may play an important role in migraine pathogenesis.
Slow IPSC kinetics, low levels of α1 subunit expression and paired‐pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus
Authors: Jüttner René , Meier Jochen , Grantyn Rosemarie 
Published: March 2003

AbstractRemodelling of visual maps in the superior colliculus (SC) depends on neuronal activity. Synaptic inhibition could contribute to this process because spontaneous spike discharge in the SC was modulated by GABAA receptor activation at postnatal days (P) 1–3. To investigate the functional capacity of GABAergic synaptic transmission at this early stage of development, whole‐cell patch‐clamp recordings were made from wide field neurons (WFNs) in horizontal slices comprising the superficial grey layer of the SC. Focal stimulation in the vicinity of WFNs evoked tetrodotoxin‐sensitive stimulus‐locked inhibitory postsynaptic currents (eIPSCs). The failure rate of eIPSCs was low (≈ 0.2), and the maximal amplitude of evoked unitary eIPSCs exceeded the amplitude of average miniature IPSCs (mIPSCs) by a factor of 4–5, suggesting that action potential‐mediated GABA release was more effective than spontaneous release. Some of the properties of GABAergic synaptic transmission in the neonatal SC were age‐specific. In contrast with eIPSCs in the more mature SC at P20–22, neonatal eIPSCs decayed more slowly, preferentially fluctuated in duration, not amplitude, and mostly lacked temporal summation, due to depression at shorter intervals. The paired‐pulse ratio (eIPSC2 : eIPSC1) was inversely related to the duration of eIPSCs. PCR analysis showed, in addition, that the ratio of α1 : α3 subunit expression was lower in the neonatal SC. Together, these results suggest that, at a young age, efficacy of GABAergic synaptic transmission is primarily constrained by the slow kinetics and the saturation of postsynaptic GABAA receptors.
Localized immediate early gene expression related to the strength of song learning in socially reared zebra finches
Authors: Bolhuis Johan J. , Hetebrij Elske , Den Boer‐Visser Ardie M. , De Groot Jurriaan H. , Zijlstra Guus G. O. 
Published: March 2003

AbstractRecent evidence showed that exposure of tape‐tutored zebra finch (Taeniopygia guttata castanotis) males to the tutor song involves neuronal activation in brain regions outside the conventional ‘song control pathways’, particularly the caudal part of the neostriatum (NCM) and of the hyperstriatum ventrale (CMHV). Zebra finch males were reared with a live tutor during the sensitive period for song learning. When, as adults, they were re‐exposed to the tutor song, the males showed increased expression of Fos, the protein product of the immediate early gene c‐fos, in the NCM and CMHV, compared with expression in two conventional ‘song control nuclei’, high vocal centre (HVC) and Area X. The strength of the Fos response (which is a reflection of neuronal activation) in the NCM (but not in the other three regions) correlated significantly and positively with the number of song elements that the birds had copied from the tutor song. Thus, socially tutored zebra finch males show localized neural activation in response to tutor song exposure, which correlates with the strength of song learning.
Conscious recollection and illusory recognition: an event‐related fMRI study
Authors: Von Zerssen G. Clemens , Mecklinger Axel , Opitz Bertram , Von Cramon D. Yves 
Published: March 2003

AbstractIn this event‐related functional magnetic resonance imaging (fMRI) study we examined the neuronal correlates of the subprocesses underlying recognition memory. In an explicit memory task, participants had to discriminate studied (‘old’) words from semantically related and unrelated ‘new’ (unstudied) words. We examined whether the correct rejection of semantically related words which were similar to old words, which had elicited correct responses, was based on conscious recollection of study phase information. In this task, false‐positive responses to semantically related new words can be assumed to result from the assessment of the semantic similarity between test words and studied words with minimal recollection. For correct identification of old words and correct rejection of new related words we found common activation in a variety of brain areas that have been shown to be involved in conscious recollection, among them the left middle frontal gyrus, the precuneus, the retrosplenial cortex, the left parahippocampal gyrus and the thalamus. For correct responses to old words, the frontomedian wall, the posterior cingulate cortex and the nucleus accumbens were additionally activated, suggesting an emotional contribution to these judgements. Correct rejections of related new words were associated with additional activation of the right middle frontal gyrus, suggesting higher monitoring demands for these more difficult recognition judgements. False‐positive responses to semantically related new words were associated with enhanced activation in the frontomedian wall. The results point to an important role of the prefrontal cortex as well as medial temporal and medial parietal regions of the brain in successful memory retrieval and conscious recollection.
Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man
Authors: Alekov Alexi K. , Rahman MD. Masmudur , Mitrovic Nenad , Lehmann‐Horn Frank , Lerche Holger 
Published: March 2003

AbstractGeneralized epilepsy with febrile seizures‐plus (GEFS+) is a benign Mendelian syndrome characterized by childhood‐onset febrile and afebrile seizures. Three point mutations within two voltage‐gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the β1‐subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal α‐subunit gene SCN1A. Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel α‐subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the experiments revealed a pronounced enhancement of both fast and slow inactivation and a defect of channel activation for T685M compared to wild‐type channels. Steady‐state fast and slow inactivation curves were shifted in the hyperpolarizing direction, entry into slow inactivation was threefold accelerated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. In contrast to other disease‐causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivation was the most obvious alteration in gating found for T685M, this might be the disease‐causing mechanism for that mutation. In this case, the occurrence of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.
VR1 protein expression increases in undamaged DRG neurons after partial nerve injury
Authors: Hudson L. J. , Bevan S. , Wotherspoon G. , Gentry C. , Fox A. , Winter J. 
Published: March 2003

AbstractChanges in phenotype or connectivity of primary afferent neurons following peripheral nerve injury may contribute to the hyperalgesia and allodynia associated with neuropathic pain conditions. Although earlier studies using partial nerve injury models have focused on the role of damaged fibres in the generation of ectopic discharges and pain, it is now thought that remaining undamaged fibres may be equally important. We have examined the expression of the sensory neuron‐specific cation channel Vanilloid Receptor 1 (VR1), an important transducer of noxious stimuli, in three models of nerve injury in the rat, using anatomical separation or fluorescent retrograde tracers to identify damaged or undamaged sensory neurons. After total or partial sciatic nerve transection, or spinal nerve ligation, VR1‐immunoreactivity (IR) was significantly reduced in the somata of all damaged dorsal root ganglion (DRG) neuronal profiles, compared to controls. However, after partial transection or spinal nerve ligation, VR1 expression was greater in the undamaged DRG somata than in controls. Unexpectedly, after L5 spinal nerve ligation, VR1‐IR of the A‐fibre somata increased ≈ 3‐fold in the uninjured L4 DRG compared to controls; a much greater increase than seen in the somata with C‐fibres. Furthermore, we found that VR1‐IR persisted in the transected sciatic nerve proximal to the lesion, despite its down‐regulation in the damaged neuronal somata. This persistence in the nerve proximal to the lesion after nerve section, together with increased VR1 in DRG neurons left undamaged after partial nerve injury, may be crucial to the development or maintenance of neuropathic pain.