bluuebunny/crossref_metadata_2025 huggingface dataset:
Epileptic fast activity can be explained by a model of impaired GABAergic dendritic inhibition
Authors: Wendling F. , Bartolomei F. , Bellanger J. J. , Chauvel P.
Published: March 2003

This paper focuses on high‐frequency (gamma band) EEG activity, the most characteristic electrophysiological pattern in focal seizures of human epilepsy. It starts with recent hypotheses about: (i) the behaviour of inhibitory interneurons in hippocampal or neocortical networks in the generation of gamma frequency oscillations; (ii) the nonuniform alteration of GABAergic inhibition in experimental epilepsy (reduced dendritic inhibition and increased somatic inhibition); and (iii) the possible depression of GABAA,fast circuit activity by GABAA,slow inhibitory postsynaptic currents. In particular, these hypotheses are introduced in a new computational macroscopic model of EEG activity that includes a physiologically relevant fast inhibitory feedback loop. Results show that strikingly realistic activity is produced by the model when compared to real EEG signals recorded with intracerebral electrodes. They show that, in the model, the transition from interictal to fast ictal activity is explained by the impairment of dendritic inhibition.
Altered presynaptic function in monoaminergic neurons of monoamine oxidase‐A knockout mice
Authors: Owesson Catarina Å. , Hopwood Sarah E. , Callado Luis F. , Seif Isabelle , McLaughlin Daniel P. , Stamford Jonathan A.
Published: March 2003

Monoamine oxidase‐A knockout (MAO‐A KO) mice have elevated brain serotonin (5‐HT) and noradrenaline (NA) levels, and one would therefore anticipate increased monoamine release and compensatory changes in other aspects of presynaptic monoamine function. In this study we used voltammetry in brain slices from the locus coeruleus (LC), dorsal raphe (DRN) and striatum (CPu) in 7‐week‐old MAO‐A KO and C3H control mice to measure stimulated monoamine efflux and its control by amine transporters and autoreceptors. In LC, peak NA efflux on stimulation (99 pulses, 100 Hz) was higher in MAO‐A KO than C3H mice (938 ± 58 nm cf. 511 ± 42 nm; P < 0.001). The NA uptake half time (t½) was longer in MAO‐A KO than in C3H mice (6.0 ± 0.9 s cf. 1.9 ± 0.3 s; P < 0.001) and the selective NA reuptake inhibitor desipramine (50 nm) had a smaller effect in MAO‐A KO mice. NA transporter binding was significantly lower in the LC of MAO‐A KO mice compared to C3H controls (P < 0.01) but not in the DRN. The α2 agonist dexmedetomidine (10 nm) decreased stimulated NA efflux more in C3H than in MAO‐A KO mice (73.3% cf. 29.6% inhibition, P < 0.001). In DRN, peak 5‐HT efflux on stimulation (99 pulses, 100 Hz) was greater (P < 0.01) in MAO‐A KO (262 ± 44 nm) than C3H mice (157 ± 16 nm). Moreover, 5‐HT uptake t½ was longer (P < 0.05) in MAO‐A KO than in C3H mice (8.8 ± 1.1 s cf. 4.9 ± 0.6 s, P < 0.05) and the effect of citalopram (75 nm) was attenuated in MAO‐A KOs. Serotonin transporter binding was also lower in both the DRN and LC of MAO‐A KO mice. The 5‐HT1A agonist 8‐OH‐DPAT (1 µm) decreased 5‐HT efflux more in C3H than in MAO‐A KO mice (38.3% inhibition cf. 21.6%, P < 0.001). In contrast, there were no significant differences between MAO‐A KO and C3H mice in CPu dopamine efflux and uptake and the effect of the D2/3 agonist quinpirole was similar in the two strains. In summary, MAO‐A KO mice show major dysregulation of monoaminergic presynaptic mechanisms such as autoreceptor control and transporter kinetics.
Synaptic localization of membrane‐associated guanylate kinase‐interacting protein mediated by the pleckstrin homology domain
Authors: Iida Junko , Nishimura Wataru , Yao Ikuko , Hata Yutaka
Published: March 2003

Membrane‐associated guanylate kinase‐interacting protein (MAGUIN) has been identified as a protein binding postsynaptic density (PSD)‐95 and synaptic scaffolding molecule (S‐SCAM). MAGUIN has one sterile α motif, one conserved region in connector enhancer of ksr (Cnk) (CRIC), one PSD‐95/Dlg‐A/ZO‐1 (PDZ) and one pleckstrin homology (PH) domain. There are two isoforms, MAGUIN‐1 and ‐2. MAGUIN‐1 binds the PDZ domains of PSD‐95 and S‐SCAM by the C‐terminus, whereas MAGUIN‐2 does not bind to PSD‐95 or S‐SCAM. Here, we have determined that MAGUIN‐2 is also localized at synapses and that the synaptic localization of MAGUIN depends on the pleckstrin homology domain. The overexpressed C‐terminal PDZ‐binding region inhibits the synaptic targeting of PSD‐95. Furthermore, the synaptic targeting of MAGUIN does not require N‐methyl‐d‐aspartate (NMDA) receptor activity. These findings suggest that MAGUIN‐1 and ‐2 are recruited to synapses by the PH domain and that MAGUIN‐1 subsequently interacts with PSD‐95 at synapses.
Metabotropic glutamate receptors are involved in amygdaloid plasticity
Authors: Fendt Markus , Schmid Susanne
Published: March 2003

The amygdala plays an important role in emotional learning. Synaptic plasticity underlying the acquisition of conditioned fear occurs in the lateral nucleus of the amygdala: long‐term potentiation (LTP) of synapses in the pathway of the conditioned stimulus (CS) has shown to be a neural correlate of this kind of emotional learning. The present study is based on previous results of our laboratory showing an important role of the metabotropic glutamate receptor subtype 5 (mGluR5) in fear conditioning. Here, we explored whether mGlu5 receptors within the lateral nucleus of the amygdala are involved in the plasticity underlying fear conditioning. We used an in vivo approach investigating the acquisition, consolidation and expression of conditioned fear by the fear‐potentiated startle paradigm and by the inhibition of motor activity during CS presentation. Additionally, we used an in vitro approach inducing LTP in the lateral amygdala by patch‐clamp recordings in rat brain slices. Acquisition of conditioned fear, but not consolidation and expression, was blocked by intra‐amygdaloid injections of the specific mGluR5 antagonist 2‐methyl‐6‐(phenylethynyl) pyridine hydrochloride (MPEP) in vivo. Furthermore, induction of amygdaloid LTP but not synaptic transmission was disrupted by MPEP application in vitro. These experiments show for the first time in vivo and in vitro that mGluR5 receptors are necessary for plasticity in the amygdala.
Strain differences in σ1 receptor‐mediated behaviours are related to neurosteroid levels
Authors: Phan Vân‐Ly , Urani Alexandre , Romieu Pascal , Maurice Tangui
Published: March 2003

The sigma1 (σ1) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the σ1 receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in σ1 receptor‐mediated behaviours could be observed among mouse strains, in relation with differences in either σ1 receptor expression or steroid levels. The σ1‐receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo[3H](+)‐SKF‐10 047 binding to σ1 receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [3H](+)‐SKF‐10 047 binding only in Swiss. The behavioural efficacy of the selective σ1 agonists igmesine and PRE‐084 – reversion of the scopolamine‐induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test – were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous σ1 antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of σ1‐receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine‐induced reward properties, known to critically involve the σ1 receptor.
Caffeine stimulates Ca2+entry through store‐operated channels to activate tyrosine hydroxylase in bovine chromaffin cells
Authors: McKenzie Sacha , Marley Philip D.
Published: March 2003

The ability of caffeine‐induced store Ca2+mobilization to activate tyrosine hydroxylase was studied in bovine adrenal chromaffin cells. Caffeine increased tyrosine hydroxylase activity over 10 min with an EC50of 3 mmand maximum effect at 20 mm. The maximum response to caffeine was substantial, being almost one third that of the strongest agonists acetylcholine and PACAP‐27, about half that for K+and similar to that for histamine. In contrast, catecholamine secretion evoked by caffeine was small, being less than 10% of the response to strong agonists. Caffeine‐induced tyrosine hydroxylase activation was not mimicked or prevented by phosphodiesterase inhibition with isobutylmethylxanthine, nor was it mimicked by an equimolar concentration of sucrose. However, the effect of caffeine was prevented by depleting intracellular Ca2+stores by thapsigargin pretreatment, and reduced substantially by removing extracellular Ca2+, by blocking Ca2+channels with Co2+or Ni2+, or by inhibiting store‐operated channels with 2‐aminoethyl diphenylborate. It was not affected by inhibiting Ca2+entry through voltage‐operated Ca2+‐channels or by tetrodotoxin. The effect of caffeine was mimicked by acute thapsigargin treatment or by depleting intracellular Ca2+stores in Ca2+‐free buffer and then reintroducing extracellular Ca2+. The results indicate that mobilizing store Ca2+with caffeine is a very effective mechanism for activating tyrosine hydroxylase and that the majority of this response depends on extracellular Ca2+entry through store‐operated channels. They also suggest that extracellular Ca2+entry through such channels regulates cellular responses differently to Ca2+entry through voltage‐operated Ca2+channels.
Molecular‐feature domains with posterodorsal–anteroventral polarity in the symmetrical sensory maps of the mouse olfactory bulb: mapping of odourant‐induced Zif268 expression
Authors: Inaki Koichiro , Takahashi Yuji K. , Nagayama Shin , Mori Kensaku
Published: March 2003

Individual glomeruli in the mammalian olfactory bulb presumably represent a single type of odourant receptor. Thus, the glomerular sheet provides odourant receptor maps at the surface of the olfactory bulb. To understand the basic spatial organization of the olfactory sensory maps, we first compared the spatial distribution of odourant‐induced responses measured by the optical imaging of intrinsic signals with that detected immunohistochemically by expressions of Zif268, one of the immediate early gene products in juxtaglomerular cells. In the dorsal surface of the bulb, we detected a clear correlation in the spatial pattern between these responses. In addition, the molecular‐feature domains and their polarities (spatial shifts of responses with an increase in carbon chain length) that were defined by the optical imaging method could be also detected by the Zif268 mapping method. We then mapped the Zif268 signals over the entire olfactory bulb using a homologous series of fatty acids and aliphatic alcohols as stimulus odourants. We superimposed the Zif268 signals onto the standard unrolled map with the help of cell adhesion molecule compartments. Each odourant typically elicited two pairs of clusters of dense Zif268 signals. The results showed that molecular‐feature domains and their polarities were arranged symmetrically at stereotypical positions in a mirror‐image fashion between the lateral and the medial sensory maps. The polarity of each domain was roughly in parallel with the posterodorsal–anteroventral axis that was defined by the cell adhesion molecule compartments. These results suggest that the molecular‐feature domain with its fixed polarity is one of the basic structural units in the spatial organization of the odourant receptor maps in the olfactory bulb.
Upregulation and activation of the Nrf‐1 transcription factor in the lesioned hippocampus
Authors: Hertel Moritz , Braun Susanne , Durka Silke , Alzheimer Christian , Werner Sabine
Published: March 2003

The Nrf‐1 and Nrf‐2 transcription factors play a pivotal role in the cellular defence against the toxic effects of reactive oxygen species (ROS). Although ROS are key effectors of neuronal death after ischaemic and traumatic brain injury, it is not known whether Nrf‐1 and Nrf‐2 are involved in neuroprotective signalling. Here, we analysed the temporal and spatial expression pattern of Nrf‐1 and Nrf‐2 after unilateral excitotoxic lesion of mouse hippocampus. In marked contrast to previous in vitro studies, where upregulation of these transcription factors on the mRNA level was never detected, we found a strong induction of Nrf‐1 mRNA and protein expression in neurons of the lesioned hippocampus, accompanied by a weak elevation of Nrf‐2 mRNA levels. Nrf‐1 predominantly localized to the nucleus in the injured hippocampus. Furthermore, expression of the cytoprotective enzyme, heme oxygenase‐1, a major target of Nrf‐1 and Nrf‐2 action, was coregulated with Nrf‐1 in the same hippocampal neurons, suggesting that Nrf‐1 is functionally active. Because Nrf‐1 and Nrf‐2 are potent inducers of various cytoprotective proteins, our data suggest a role of Nrf‐1 and Nrf‐2 in neuronal survival after acute brain injury.
Laterality of the pontocerebellar projections in the rat
Authors: Serapide M. F. , Zappalà A. , Parenti R. , Pantò M. R. , Cicirata F.
Published: March 2003

This study aimed to investigate the trajectory of fibres from the pontine nuclei that reach the two sides of the cerebellum. Injections of biotinylated dextran amine (BDA) were made within the basilar pontine nuclei (BPN) and the nucleus reticularis tegmenti pontis (NRTP) in one side of rats with electrolytic injury of the middle cerebellar peduncle (MCP), ipsilateral or contralateral to the side of injection. Fibres were traced from the pontine nuclei (BPN and NRTP) to both sides of the cerebellum passing through the respective MCPs. The study carried out in rats with injury to one peduncle showed projections segregated to the half‐side of the cerebellum innervated by the intact peduncle. The laterality observed was confirmed by a retrograde tracer study. In fact, injections of different fluorescent tracers in rats with injury of single MCP showed that in the pontine nuclei only cell bodies stained by the tracer injected in the half‐cerebellum ipsilateral to the intact peduncle. Finally, similar injections (i.e. different fluorescent tracers in symmetric areas of the cerebellar cortex) in the cerebellum of intact brain rats showed that BPN and NRTP differ for the laterality of their projections. In fact, 82% of BPN cells project contralaterally and 18% ipsilaterally, whereas 60% of NRTP cells project contralaterally and 40% ipsilaterally. In conclusion, this study showed that the MCPs receive fibres from the pontine nuclei of both sides and project to the ipsilateral half of the cerebellum and that different contingents of projections to the two sides of the cerebellum arise from BPN and NRTP.
Mapping the oculomotor system: the power of transneuronal labelling with rabies virus
Authors: Graf Werner , Gerrits Nicolaas , Yatim‐Dhiba Najiya , Ugolini Gabriella
Published: March 2003

Neuronal networks underlying and related to horizontal eye movements were visualized by retrograde transneuronal tracing with rabies virus from the left medial rectus muscle in guinea pigs. Time‐sequenced labelling revealed distinct circuitries involved in particular oculomotor functions, i.e. vestibulo‐ocular reflex and saccade generation (brainstem circuitry), adaptive plasticity (cerebellar modules) and possibly motivation and navigation (limbic, hippocampal and cortical structures). Our results provide a first comprehensive road map of the oculomotor system that is unsurpassed by any previous tracing study. We report a number of unexpected findings that illustrate a much vaster and more complicated network for the control of the relatively simple horizontal eye movements than had been envisioned previously.
Cell‐specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle
Authors: Boulland Jean‐Luc , Osen Kirsten K. , Levy Line M. , Danbolt Niels Christian , Edwards Robert H. , Storm‐Mathisen Jon , Chaudhry Farrukh A.
Published: March 2003

Glutamine is involved in a variety of metabolic processes, including recycling of the neurotransmitters glutamate and γ‐aminobutyric acid (GABA). The system N transporter SN1 mediates efflux as well as influx of glutamine in glial cells [Chaudhry et al. (1999), Cell, 99, 769–780]. We here report qualitative and quantitative data on SN1 protein expression in rat. The total tissue concentrations of SN1 in brain and in kidney are half and one‐quarter, respectively, of that in liver, but the average concentration of SN1 could be higher in astrocytes than in hepatocytes. Light and electron microscopic immunocytochemistry shows that glutamatergic, GABAergic and, surprisingly, purely glycinergic boutons are ensheathed by astrocytic SN1 laden processes, indicating a role of glutamine in the production of all three rapid transmitters. A dedication of SN1 to neurotransmitter recycling is further supported by the lack of SN1 immunoreactivity in oligodendrocytes (cells rich in glutamine but without perisynaptic processes). All neuronal structures appear unlabelled implying that a different protein mediates glutamine uptake into nerve endings. In several regions, SN1 immunoreactivity is higher in association with GABAergic than glutamatergic synapses, in agreement with observations that exogenous glutamine increases output of transmitter glutamate but not GABA. Nerve terminals with low transmitter reuptake or high prevailing firing frequency are associated with high SN1 immunoreactivity in adjacent glia. Bergmann glia and certain other astroglia contain very low levels of SN1 immunoreactivity compared to most astroglia, including retinal Müller cells, indicating the possible existence of SN isoforms and alternative mechanisms for transmitter recycling.
Activity‐dependent receptive field changes in the surround of adult cat visual cortex lesions
Authors: Schweigart Georg , Eysel Ulf T.
Published: March 2003

Extracellular single cell spike activity was recorded in the visual cortex of anaesthetized adult cats at identical sites before and 2 days after focal excitotoxic lesions induced by injections of ibotenic acid. In the surround of the lesions (up to 5 mm from the border of the lesion), the average postlesion receptive field (RF) sizes were not different from the prelesion RFs. However, RFs of neurons with increased postlesion excitability were slightly enlarged; such neurons were mainly found close to the anterior border of the lesion (≤ 1 mm). After applying a visual training procedure for 1 h to the postlesion RFs (repetitive, synchronous stimulation of a part of the RF and the neighbouring unresponsive part of the visual field), there was a small (0.4–0.8°) but significant and specific increase of RF size in about half of the tested neurons. This RF enlargement was similar to that observed with the same training procedure in the visual cortex of normal cats. Thus, small RF changes can be induced by visual stimulation within one hour in normal cells as well as in cells at the border of cortical lesions. Any differences between normal and lesioned animals appear to be related to lesion‐induced changes of excitability.
Analysis of the function of GABAB receptors on inhibitory afferent neurons of Purkinje cells in the cerebellar cortex of the rat
Authors: Than Marta , Szabo Bela
Published: March 2003

Purkinje cells, the output neurons of the cerebellar cortex, receive inhibitory input from basket, stellate and neighbouring Purkinje cells. The aim of the present study was to clarify the role of GABAB receptors on neurons giving inhibitory input to Purkinje cells. In sagittal slices prepared from the cerebellar vermis of the rat, the GABAB receptor agonist baclofen lowered the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded in Purkinje cells. These effects were prevented by the GABAB receptor antagonist CGP 55845. Two mechanisms were involved in the depression of the inhibitory input to Purkinje cells. The first mechanism was suppression of the firing of basket, stellate and Purkinje cells. The second mechanism was presynaptic inhibition of GABA release from terminals of the afferent axons. This was indicated by the finding that baclofen decreased the amplitude of IPSCs occurring in Purkinje cells synchronously with action potentials recorded in basket cells. A further support for the presynaptic inhibition is the observation that baclofen decreased the amplitude of autoreceptor currents which are due to activation of GABAA autoreceptors at axon terminals of basket cells by synaptically released GABA. The presynaptic inhibition was partly due to direct inhibition of the vesicular release mechanism, because baclofen lowered the frequency of miniature IPSCs recorded in Purkinje cells in the presence of cadmium and in the presence of tetrodotoxin plus ionomycin. The results show that activation of GABAB receptors decreased GABAA receptor‐mediated synaptic input to cerebellar Purkinje cells both by lowering the firing rate of the inhibitory input neurons and by inhibiting GABA release from their axon terminals with a presynaptic mechanism.
Programmed cell death in the neurulating embryo is prevented by the chaperone heat shock cognate 70
Authors: Rubio Eva , Valenciano Ana I. , Segundo Carmen , Sánchez Noelia , De Pablo Flora , De La Rosa Enrique J.
Published: March 2003

Neuronal cell death is a genuine developmental process, with precise regulation and defined roles. In striking contrast, characterization of cell death that occurs at early stages of neural development is very limited. We previously showed that embryonic proinsulin increases the level of the chaperone heat shock cognate 70 (Hsc70) and reduces the incidence of apoptosis in the neurulating chick embryo [de la Rosa, et al. (1998), Proc. Natl. Acad. Sci. USA, 95, 9950]. We now demonstrate that Hsc70 is directly involved in cell survival during neurulation, as specific downregulation of endogenous Hsc70 by antisense oligodeoxynucleotide interference provoked an increase in apoptosis both in vitro and in ovo. In parallel, activation of caspase‐3 was increased after hsc70 antisense oligodeoxynucleotide treatment. Dead cells were located mostly in the developing nervous system, distributed in areas where the incidence of cell death was high. These areas coincided both in vivo and under different death‐inducing conditions, including antisense interference and growth factor deprivation. Hsc70 immunostaining was strong in at least some areas of high cell death. Apoptotic cells within these areas presented undetectable Hsc70 levels, however, suggesting that this protein acts as an intrinsic protector of neuroepithelial and neural precursor cells.
Modulation of Ca2+currents in rat thalamocortical relay neurons by activity and phosphorylation
Authors: Meuth Sven , Pape Hans‐Christian , Budde Thomas
Published: March 2003

Rhythmic low and high frequency activity in thalamocortical networks depend critically on activation of low‐ and high‐voltage‐activated (LVA, HVA) Ca2+currents. In order to test whether Ca2+currents are modified during repetitive activation, acutely isolated thalamocortical relay neurons of rats, at postnatal days 12 (P12) to P20, were investigated using patch‐clamp, Ca2+imaging and Western blot techniques. High‐voltage‐activated, but not LVA Ca2+currents were reduced significantly during 2 Hz stimulation. Ca2+imaging experiments demonstrated a close correlation between the increase in intracellular Ca2+levels and the decrease in HVA Ca2+current amplitudes. Further examination of HVA Ca2+currents revealed a ‘U‐shaped’ inactivation curve and a time‐dependent inactivation process that could be described by a two‐exponential function. The ‘U‐shape’ was significantly reduced, current amplitude was increased significantly and time‐dependent inactivation revealed a one‐exponential decline with Ba2+as the charge carrier, following activation of the cAMP/PKA pathway, and following application of phosphatase inhibitors (ascomycin, calyculin A). Western blot analysis and the effect of ascomycin indicated an involvement of calcineurin in the inactivation process. Isolation of HVA Ca2+current components by subtype‐specific blockers revealed that changes in time‐dependent inactivation, inactivation curve and current amplitude were carried mainly by L‐type and N‐type Ca2+currents. Furthermore, Ca2+‐dependent inactivation was operative during stimulation protocols mimicking tonic action potential firing. These data indicate a modulation of L‐ and N‐type Ca2+channels by phosphorylation, resulting jointly in an increased intracellular Ca2+influx during activity of the ascending brainstem system, the latter occurring during states of wakefulness.
Selective chronic stress‐induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress‐related cortical pathology?
Authors: Trentani A. , Kuipers S. D. , Ter Horst G. J. , Den Boer J. A.
Published: March 2003

Stress has been shown to affect brain structural plasticity, promote long‐term changes in multiple neurotransmitter systems and cause neuronal atrophy. However, the mechanisms involved in these stress‐related neural alterations are still poorly understood. Mitogen‐activated protein kinase (MAPK) cascades play a crucial role in the transduction of neurotrophic signal from the cell surface to the nucleus and are implicated in the modulation of synaptic plasticity and neuronal survival. An intriguing possibility is that stress might influence brain plasticity through its effects on selective members of such intracellular signalling cascades responsible for the transduction of neurotrophin signals. Here, we have investigated the effects of stress on the expression of three members of the MAPK/extracellular‐regulated kinase (ERK) pathway such as phospho‐ERK1, phospho‐ERK2 and phospho‐cAMP/calcium‐responsive element‐binding protein (CREB) in the adult rat brain. Male rats were subjected to mild footshocks and the patterns of protein expression were analysed after 21 consecutive days of stress. We found that chronic stress induced a pronounced and persistent ERK1/2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction of phospho‐CREB expression in several cortical and subcortical regions. We hypothesized that defects in ERK signalling regulation combined with a reduced phospho‐CREB activity may be a crucial mechanism by which sustained stress may induce atrophy of selective subpopulations of vulnerable cortical neurons and/or distal dendrites. Thus, ERK‐mediated cortical abnormalities may represent a specific path by which chronic stress affects the functioning of cortical structures and causes selective neural network defects.
Creatine kinase B‐driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility
Authors: Jost Carolina R. , Van der Zee Catharina E. E. M. , In ‘t Zandt Henricus J. A. , Oerlemans Frank , Verheij Michel , Streijger Femke , Fransen Jack , Heerschap Arend , Cools Alexander R. , Wieringa Bé
Published: March 2003

Creatine kinases are important in maintaining cellular‐energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine‐like compounds. Herein we examine whether ablation of the cytosolic brain‐type creatine kinase (B‐CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B‐CK (B‐CK–/–) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra‐ and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr ⇆ ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B‐CK–/– animals showed diminished open‐field habituation. In the water maze, adult B‐CK–/– mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24‐month‐old, aged B‐CK–/– mice, on top of the age‐related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole‐induced seizures (creating a high‐energy demand) was observed in B‐CK–/– mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho‐creatine shuttle provides compensation for the loss of B‐CK in the brain. Our studies indicate a role for the creatine–phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B‐CK can be compensated for by other systems in the versatile and robust metabolic‐energy network of the brain.
Metabotropic glutamate receptors mediate expression of LTP in slices of rat visual cortex
Authors: Huemmeke Markus , Eysel Ulf T. , Mittmann Thomas
Published: March 2003

Long‐term‐potentiation (LTP) can be induced by application of a standard theta‐burst stimulation protocol in slice preparations of the neocortex. This type of LTP is known to be dependent on the activation of NMDA receptors. The present study used specific experimental conditions to evoke a non‐NMDA receptor mediated type of LTP. By use of weak theta‐burst stimulation (wTBS) we describe a non‐NMDA receptor dependent LTP in rat visual cortex in vitro, which is sensitive to an antagonist of metabotropic glutamate receptors (mGluR). In slices of the visual cortex we stimulated ascending inputs in cortical layer IV and recorded extracellular field potentials (FPs) from cortical layers II/III. In disinhibited slices (with 1 µm picrotoxin), a wTBS induced LTP to 138% of control. The expression of this potentiation was insensitive to the NMDA‐receptor antagonist, D‐AP5, but could be abolished by application of the mGluR antagonist MCPG. These data suggest an NMDA‐independent mechanism for LTP induction in the visual cortex which can be observed in layer II/III neurons.
Contralateral inhibition as a sensory bias: the neural basis for a female preference in a synchronously calling bushcricket, Mecopoda elongata
Authors: Römer Heiner , Hedwig Berthold , Ott Swidbert R.
Published: March 2003

Imperfect synchrony between male calls occurs widely in acoustically courting crickets and bushcrickets. Males which are able to establish the temporal leadership usually attract more females in choice experiments but the proximate mechanism for this precedence effect is unknown. Here we show that contralateral inhibition, the neural basis for lateral contrast enhancement in the auditory pathways of insects and vertebrates, is also the probable proximate neural mechanism for this female preference. We recorded simultaneously from a pair of identified auditory interneurons in the synchronizing bushcricket Mecopoda elongata. When two identical acoustic stimuli are presented from opposite directions, one preceding the other by 120 ms, the neural representation within the receiver is far stronger for the leader signal. This results from a suppression of the neural response to the follower chirp by reciprocal contralateral inhibition. The advantage of the representation of the leader is 2–3‐fold with time delays between 70 and 130 ms; the most clear‐cut female preferences have also been found with such delays in previous behavioural experiments. In time–intensity trading experiments, a lead by 120 ms could only be compensated for by increasing the amplitude of the follower signal by 7–11 dB. We discuss contralateral inhibition in auditory systems as a sensory bias that results in female preference for leading signals, with important evolutionary consequences for male calling strategies.
The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projections
Authors: Sarter Martin , Bruno John P.
Published: March 2003

At least half of the basal forebrain neurons which project to the cortex are GABAergic. Whilst hypotheses about the attentional functions mediated by the cholinergic component of this corticopetal projection system have been substantiated in recent years, knowledge about the functional contributions of its GABAergic branch has remained extremely scarce. The possibility that basal forebrain GABAergic neurons that project to the cortex are selectively contacted by corticofugal projections suggests that the functions of the GABAergic branch can be conceptualized in terms of mediating executive aspects of cognitive performance, including the switching between multiple input sources and response rules. Such speculations gain preliminary support from the effects of excitotoxic lesions that preferentially, but not selectively, target the noncholinergic component of the basal forebrain corticopetal system, on performance in tasks involving demands on cognitive flexibility. Progress in understanding the cognitive functions of the basal forebrain system depends on evidence regarding its main noncholinergic components, and the generation of such evidence is contingent on the development of methods to manipulate and monitor selectively the activity of the GABAergic corticopetal projections.
Endogenous histamine in the medial septum–diagonal band complex increases the release of acetylcholine from the hippocampus: a dual‐probe microdialysis study in the freely moving rat
Authors: Bacciottini Lucia , Passani Maria Beatrice , Giovannelli Lisa , Cangioli Iacopo , Mannaioni Pier Francesco , Schunack Walter , Blandina Patrizio
Published: March 2003

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c‐fos in the medial septum–diagonal band (MSA‐DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA‐DB neurons, we used the dual‐probe microdialysis technique to apply drugs to the MSA‐DB and record the induced effects in the projection area. Perfusion of MSA‐DB with high‐KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra‐MSA‐DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA‐DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA‐DB, increased the release of hippocampal ACh, whereas R‐α‐methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA‐DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c‐fos immunoreactivity were significantly more numerous in ciproxifan‐ or thioperamide‐treated rats than in controls, although no colocalization of anti‐c‐fos and anti‐ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.
Intrinsic optical signals in the dorsal horn of rat spinal cord slices elicited by brief repetitive stimulation
Authors: Asai Tatsuya , Kusudo Kei , Ikeda Hiroshi , Murase Kazuyuki
Published: March 2003

With repetitive electrical stimulation of the dorsal root (20 Hz for 1 s at C‐fibre strength), intrinsic optical signals (IOSs), measured as changes in light transmittance, were recorded in the superficial dorsal horn of rat spinal cord slices using a photodiode array imaging device. The mechanism underlying the induction of IOSs was investigated. IOSs elicited by brief repetitive stimulation persisted for 1–2 min and were decreased by reducing external Cl– concentration or by cation–chloride cotransport inhibitors. Furosemide was most effective whilst bumetanide was least effective among the inhibitors tested. A 1‐min elevation of external K+ concentration evoked IOSs in the dorsal horn in the absence of stimulation, and K+‐induced IOSs were inhibited by furosemide. These results suggest that the uptake of excess K+ via the furosemide‐sensitive, cation–chloride cotransporters underlies the induction of the IOSs. One‐minute exposure to hypotonic solutions, which would cause cell swelling, induced IOSs in the superficial dorsal horn. Whilst osmotic‐induced IOSs were not affected by furosemide, they were inhibited by HgCl2 in a 2‐mercaptoethanol‐sensitive manner. The stimulation‐induced IOSs were similarly depressed by HgCl2. In contrast, voltage‐sensitive dye signals and field potentials, evoked by single electrical stimuli, were significantly less affected by HgCl2. These results suggest that there is a specialized water transport pathway in the superficial dorsal horn, and that IOSs elicited by brief repetitive activation of C‐fibres are attributable to cell swelling caused by water influx through this pathway, as an osmotic gradient is established by the uptake of K+ via the furosemide‐sensitive cotransporters.
Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia‐reperfusion brain injury in the rat
Authors: Tarozzo Glauco , Campanella Marilena , Ghiani Michela , Bulfone Alessandro , Beltramo Massimiliano
Published: March 2003

Fractalkine is a neuronally expressed chemokine that acts through its G‐protein‐coupled receptor CX3CR1, localized on microglial and immune cells. Fractalkine might be involved in neuroinflammatory processes secondary to neuronal damage, which normally occur in a time frame of days after ischaemia. We evaluated by in situ hybridization and immunohistochemistry the expression of fractalkine and CX3CR1 in the rat brain, after a transient occlusion of the middle cerebral artery. We found that at 12 h after ischaemia neuronal fractalkine expression was transiently increased in scattered necrotic neurons of the cortex and lost from the ischaemic striatum. At 24 and 48 h after ischaemia, fractalkine immunoreactivity was strongly increased in morphologically intact cortical neurons of the ischaemic penumbra where also the stress‐inducible HSP‐72 was strongly up‐regulated. The intensity of fractalkine immunoreactivity of neurons in the penumbra returned to basal levels at 7 days after ischaemia. Fractalkine synthesis was also induced in endothelial cells of the infarcted area, at 48 h and 7 days after ischaemia. CX3CR1 expression was detected in the activated microglial cells of the ischaemic tissue 24 and 48 h after ischaemia, and became strongly up‐regulated in macrophages/phagocytic microglia inside the infarcted tissue 7 days after ischaemia. These data suggest that fractalkine may participate in the activation and chemoattraction of microglia into the infarcted tissue, and contribute to the control of leucocyte trafficking from blood vessels into the injured area.
NMDA receptor‐mediated metaplasticity during the induction of long‐term depression by low‐frequency stimulation
Authors: Mockett Bruce , Coussens Christine , Abraham Wickliffe C.
Published: March 2003

Metaplasticity refers to the activity‐dependent modification of the ability of synapses to undergo subsequent synaptic plasticity. Here, we have addressed the question of whether metaplasticity contributes to the induction of long‐term depression (LTD) by low‐frequency stimulation (LFS). The experiments were conducted using standard extracellular recording techniques in stratum radiatum of area CA1 in hippocampal slices made from adult Sprague–Dawley rats. The degree of LTD induction was found to be a nonlinear function of the number of pulses during a 1‐Hz LFS. Little LTD was observed following 600 or 900 pulses, but a significant LTD occurred following 1200 pulses of LFS, whether delivered in one episode, or in two bouts of 600 pulses given 10 min apart. A similar pattern was observed for 3 Hz LFS. The data support the suggestion that pulses occurring early in the LFS train prime synapses for LTD induction, as triggered by later occurring stimuli. The priming effect lasted at least 120 min, when tested by giving two bouts of 1 Hz LFS (600 pulses each) at different intervals. Neither heterosynaptic nor homosynaptic stimulation by itself was sufficient to prime LTD. However, a combination of the stimuli, induced by increased stimulus strength during the LFS, appeared necessary for inducing the effect. An N‐methyl‐d‐aspartate (NMDA) receptor antagonist markedly reduced total LTD induction, regardless of whether it was administered during the first or second LFS in a protocol employing two bouts of 600 pulse LFS, 30 min apart. These findings strongly support the hypothesis that NMDA receptor‐dependent metaplasticity processes contribute to the induction of LTD during standard LFS protocols.
The basolateral complex of the amygdala is necessary for acquisition but not expression of CS motivational value in appetitive Pavlovian second‐order conditioning
Authors: Setlow Barry , Gallagher Michela , Holland Peter C.
Published: March 2003

The basolateral complex of the amygdala (ABL) is involved in processing information about stimulus motivational value. However, it is not clear whether the ABL is critical for acquisition, maintenance, or expression of this information. Our previous work has shown that ABL lesions made prior to training, block acquisition of an appetitive Pavlovian second‐order conditioning task, in which performance is thought to depend on the acquisition of motivational (conditioned reinforcement) value by the first‐order conditioned stimulus (CS). The present experiments examined the effects of ABL lesions made after first‐order conditioning, when the CS acquires motivational value, but before second‐order conditioning, the test for acquired value of that CS. Rats received pairings of a visual CS with a food reinforcer. They then received bilateral sham or excitotoxic lesions of the ABL. After recovery, they received pairings of a second‐order auditory CS with the previously conditioned visual CS. In two experiments, both sham and lesioned rats acquired normal second‐order conditioned behaviours. Some of the same rats were then given another round of second‐order conditioning with novel CSs. In this case, when first‐order training occurred after surgery, some second‐order conditioned behaviours were impaired in lesioned rats. Tests of the associative underpinnings of second‐order conditioned behaviours showed that those behaviours impaired by ABL lesions were based on stimulus–response associations. The results show that although the ABL is critical for second‐order conditioning, this role is limited to acquisition of information about the motivational value of the first‐order CS, and it is not critical for maintenance of this information or for its use in forming second‐order associations.
The age‐related increase in IL‐1 type I receptor in rat hippocampus is coupled with an increase in caspase‐3 activation
Authors: Lynch Aileen M. , Lynch Marina A.
Published: March 2003

Evidence from several studies indicates that expression of interleukin‐1β (IL‐1β) and IL‐1 type I receptor is particularly high in hippocampus, and it has recently been shown that the concentration of IL‐1β is increased in the hippocampus of the aged rat. Here we report that this increase is coupled with an increase in expression of IL‐1 type I receptor and increased activity of IL‐1 receptor‐associated kinase. The evidence presented indicates that the age‐related increase in activity of the mitogen‐activated protein kinases, Jun N‐terminal kinase (JNK) and p38, was accompanied by enhanced caspase‐3 activity. Analysis of colocalization of activated caspase‐3 with activated p38 (p‐p38) suggested that p‐p38 was necessary for activation of caspase‐3; while in vitro analysis indicated that the IL‐1β‐induced increase in caspase‐3 activity was abrogated by the p38 inhibitor, SB203580. The IL‐1β‐induced increase in caspase‐3 activity in vitro was also abrogated by vasoactive intestinal peptide, which is a JNK inhibitor; however, colocalization of activated JNK (p‐JNK) and activated caspase‐3 did not clearly identify JNK as an upstream activator of caspase‐3. We propose that these changes are indicative of cell death in aged hippocampus and suggest that they contribute to the age‐related decrease in long‐term potentiation in perforant path granule cell synapses.
Expression and dendritic mRNA localization of GABAC receptor ρ1 and ρ2 subunits in developing rat brain and spinal cord
Authors: Rozzo Aldo , Armellin Mara , Franzot Jessica , Chiaruttini Cristina , Nistri Andrea , Tongiorgi Enrico
Published: March 2003

The cellular distribution of GABAC receptor ρ1 and ρ2 subunits in the rat central nervous system remains controversial. We investigated how these subunits were distributed in cerebellum, hippocampus and spinal cord at postnatal day 1, 7 or in adult life. We found that in the adult cerebellum ρ1 and ρ2 mRNAs were expressed in Purkinje cells and basket‐like cells only. In the hippocampus both subunits were expressed throughout the CA1 pyramidal layer, dentate gyrus and scattered interneurons with maximum staining intensity at P7. In the adult hippocampus in situ staining was predominantly found on interneurons. GABAC antibody labelling in P7 and adult hippocampus was largely overlapping with the in situ staining. Western blot analysis showed GABAC receptor in retina, ovary and testis. In the spinal cord the ρ2 signal was consistently stronger than ρ1 with overlapping expression patterns. At P1, the most intensely labelled cells were the motoneurons while on P7 and adult sections, interneurons and motoneurons were likewise labelled. On spinal neurons both ρ1 and ρ2 mRNAs showed somatodendritic localization, extending out for >100 µm with punctate appearance especially in adult cells. A similar spinal distribution pattern was provided with polyclonal antibody labelling, suggesting close correspondence between mRNA and protein compartmentalization. Electrophysiological experiments indicated that P1 spinal motoneurons did possess functional GABAC receptors even though GABAC receptors played little role in evoked synaptic transmission. Our results suggest a pattern of ρ1 and ρ2 subunit distribution more widespread than hitherto suspected with strong developmental regulation of subunit occurrence.