bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal structure of the co-crystal O-isopropyl phenylcarbamothioate – 4,4′-bipyridine (2/1), C15H17N2OS
Authors: Yeo Chien Ing , Tiekink Edward R.T. 
Published: April 2018

Abstract
C15H17N2OS, triclinic, P1̄ (no. 2), a = 5.8595(3) Å, b = 9.2967(4) Å, c = 14.0545(8) Å, α = 83.320(4), β = 89.240(4), γ = 74.524(4), V = 732.71(7) Å3, Z = 2, R
gt(F) = 0.0458, wR
ref(F
2) = 0.1231, T = 100 K.
Cannabinoid Receptor Agonists Inhibit Glutamatergic Synaptic Transmission in Rat Hippocampal Cultures
Authors: Shen Maoxing , Piser Timothy M. , Seybold Virginia S. , Thayer Stanley A. 
Published: April 2018

Activation of cannabinoid receptors inhibits voltage-gated Ca2+channels and activates K+channels, reminiscent of other G-protein-coupled signaling pathways that produce presynaptic inhibition. We tested cannabinoid receptor agonists for effects on excitatory neurotransmission between cultured rat hippocampal neurons. Reducing the extracellular Mg2+concentration to 0.1 mmelicited repetitive, transient increases in intracellular Ca2+concentration ([Ca2+]ispikes) that resulted from bursts of action potentials, as measured by combined whole-cell current clamp and indo-1-based microfluorimetry. Pharmacological characterization indicated that the [Ca2+]ispikes required glutamatergic synaptic transmission. Cannabinoid receptor ligands inhibited stereoselectively the frequency of [Ca2+]ispiking in the rank order of potency: CP 54,939 > CP 55,940 > Win 55,212-2 > anandamide, with EC50values of 0.36, 1.2, 2.7, and 71 nm, respectively. CP 55,940 was potent, but not efficacious, and reversed the inhibition produced by Win 55,212-2, indicating that it is a partial agonist. Inhibition of [Ca2+]ispiking by Win 55,212-2 was prevented by treatment of cultures with active, but not heat-treated, pertussis toxin. Win 55,212-2 (100 nm) inhibited stereoselectively CNQX-sensitive excitatory postsynaptic currents (EPSCs) elicited by presynaptic stimulation with an extracellular electrode, but did not affect the presynaptic action potential or currents elicited by direct application of kainate. Consistent with a presynaptic site of action, Win 55,212-2 increased both the number of response failures and the coefficient of variation of the evoked EPSCs. In contrast, cannabimimetics did not affect bicuculline-sensitive inhibitory postsynaptic currents. Thus, activation of cannabinoid receptors inhibits the presynaptic release of glutamate via an inhibitory G-protein.
[Ca2+]iElevations Detected by BK Channels during Ca2+Influx and Muscarine-Mediated Release of Ca2+from Intracellular Stores in Rat Chromaffin Cells
Authors: Prakriya Murali , Solaro Christopher R. , Lingle Christopher J. 
Published: April 2018

Submembrane [Ca2+]ichanges were examined in rat chromaffin cells by monitoring the activity of an endogenous Ca2+-dependent protein: the large conductance Ca2+- and voltage-activated K+channel (also known as the BK channel). The Ca2+and voltage dependence of BK current inactivation and conductance were calibrated first by using defined [Ca2+]isalines. This information was used to examine submembrane [Ca2+]ielevations arising out of Ca2+influx and muscarine-mediated release of Ca2+from intracellular stores. During Ca2+influx, some BK channels are exposed to [Ca2+]iof at least 60 μm. However, the distribution of this [Ca2+]ielevation is highly nonuniform so that the average [Ca2+]idetected when all BK channels are activated is only ∼10 μm. Intracellular dialysis with 1 mmor higher EGTA spares only the BK channels activated by the highest [Ca2+]iduring influx, whereas dialysis with 1 mmor higher BAPTA blocks activation of all BK channels. Submembrane [Ca2+]ielevations fall rapidly after termination of short (5 msec) Ca2+influx steps but persist above 1 μmfor several hundred milliseconds after termination of long (200 msec) influx steps. In contrast to influx, the submembrane [Ca2+]ielevations produced by release of intracellular Ca2+by muscarinic actetylcholine receptor (mAChR) activation are much more uniform and reach peak levels of 3–5 μm. Our results suggest that during normal action potential activity only 10–20% of BK channels in each chromaffin cell see sufficient [Ca2+]ito be activated.
Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease
Authors: Gómez-Isla Teresa , Price Joseph L. , McKeel Jr. Daniel W. , Morris John C. , Growdon John H. , Hyman Bradley T. 
Published: April 2018

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were ∼650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by ∼90%, and the number of neurons in layer IV decreased by ∼70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.
Total Number and Ratio of Excitatory and Inhibitory Synapses Converging onto Single Interneurons of Different Types in the CA1 Area of the Rat Hippocampus
Authors: Gulyás Attila I. , Megı́as Manuel , Emri Zsuzsa , Freund Tamás F. 
Published: April 2018

The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D28k(CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets.The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 μm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 μm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites.These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.
Intermediate Zone Cells Express Calcium-Permeable AMPA Receptors and Establish Close Contact with Growing Axons
Authors: Métin Christine , Denizot Jean-Pierre , Ropert Nicole 
Published: April 2018

Recent studies have shown that cells in the intermediate zone (IZ) of the embryonic neocortex originate in the basal telencephalon and migrate tangentially in the cortical wall (Anderson et al., 1997;Tamamaki et al., 1997; Wichterle et al., 1999). We had previously observed growing cortical axons closely apposed to calbindin-positive, tangentially oriented cells in the IZ (Métin and Godement, 1996), and it has been shown that neurites in the IZ express a glutamate transporter (Furuta et al., 1997). To test if glutamate released by corticofugal growth cones could influence the tangential IZ cells, we characterized the glutamate receptors expressed by IZ cells using patch-clamp techniques, histochemical labeling, and immunostaining on slices of embryonic mice forebrain. We show that tangential IZ cells express inwardly rectifying kainate responses, but not NMDA responses, and accumulate cobalt after AMPA receptor activation. We conclude that IZ cells express calcium-permeable AMPA receptors. This property correlates with our observation that the GluR2 subunit is not expressed in the IZ.AMPA receptors are activated by a millimolar concentration of glutamate. To know whether this high level of glutamate could occur at the surface of IZ cells, we examined contacts made by corticofugal growth cones and calbindin-positive IZ cells using electron microscopy. We show vesicle-containing neurites tightly apposed to calbindin-positive IZ cells over remarkably long length. This suggests that glutamate released by growing corticofugal axons could reach high concentrations close to AMPA receptors of tangential IZ cells and efficiently activate them to control the intracellular calcium in embryonic IZ cells.
Relationship of Activity in the Subthalamic Nucleus–Globus Pallidus Network to Cortical Electroencephalogram
Authors: Magill Peter J. , Bolam J. Paul , Bevan Mark D. 
Published: April 2018

One of the functions of the excitatory subthalamic nucleus (STN) is to relay cortical activity to other basal ganglia structures. The response of the STN to cortical input is shaped by inhibition from the reciprocally connected globus pallidus (GP). To examine the activity in the STN–GP network in relation to cortical activity, we recorded single and multiple unit activity in STN and/or GP together with cortical electroencephalogram in anesthetized rats during various states of cortical activation.During cortical slow-wave activity (SWA), STN and GP neurons fired bursts of action potentials at frequencies that were similar to those of coincident slow (∼1 Hz) and spindle (7–14 Hz) cortical oscillations. Spontaneous or sensory-driven global activation was associated with a reduction of SWA and a shift in STN–GP activity from burst- to tonic- or irregular-firing. Rhythmic activity in STN and GP neurons was lost when the cortex was inactivated by spreading depression and did not resume until SWA had recovered.Although rhythmic STN–GP activity was correlated with SWA, the phase relationships of activities of neurons within the STN and GP and between the nuclei were variable. Even when neurons displayed synchronous bursting activity, correlations on the millisecond time scale, which might indicate shared synaptic input, were not observed.These data indicate that (1) STN and GP activity is intimately related to cortical activity and hence the sleep–wake cycle; (2) rhythmic oscillatory activity in the STN–GP network in disease states may be driven by the cortex; and (3) activity of the STN–GP network is regulated in space in a complex manner.
Expression of Kv1 Potassium Channels in Mouse Hippocampal Primary Cultures: Development and Activity-Dependent Regulation
Authors: Grosse Gisela , Draguhn Andreas , Höhne Lysann , Tapp Rosemarie , Veh Ruediger W. , Ahnert-Hilger Gudrun 
Published: April 2018

Excitability and discharge behavior of neurons depends on the highly variable expression pattern of voltage-dependent potassium (Kv) channels throughout the nervous system. To learn more about distribution, development, and activity-dependent regulation of Kv channel subunit expression in the rodent hippocampus, we studied the protein expression of members of the Kv1 subfamily in mouse hippocampusin situand in primary cultures.In adult hippocampus, Kv1 (1–6) channel α-subunits were present, whereas at postnatal day 2, none of these proteins could be detected in CA1–CA3 and dentate gyrus. Kv1.1 was the first channel to be observed at postnatal day 6. The delayed postnatal expression and most of the subcellular distribution observed in hippocampal sections were mimicked by cultured hippocampal neurons in which Kv channels appeared only after 10 daysin vitro. This developmental upregulation was paralleled by a dramatic increase in total K+current, as well as an elevated GABA release in the presence of 4-aminopyridine. Thus, the developmental profile, subcellular localization, and functionality of Kv1 channels in primary culture of hippocampus closely resembles thein situsituation.Impairing secretion by clostridial neurotoxins or blocking activity by tetrodotoxin inhibited the expression of Kv1.1, Kv1.2, and Kv1.4, whereas the other Kv1 channels still appeared. This activity-dependent depression was only observed before the initial appearance of the respective channels and lost after they had been expressed.Our data show that hippocampal neurons in culture are a convenient model to study the developmental expression and regulation of Kv1 channels. The ontogenetic regulation and the activity-dependent expression of Kv1.1, Kv1.2, and Kv1.4 indicate that neuronal activity plays a crucial role for the development of the mature Kv channel pattern in hippocampal neurons.
Thrombomodulin as a New Marker of Lesion-Induced Astrogliosis: Involvement of Thrombin through the G-Protein-Coupled Protease-Activated Receptor-1
Authors: Pindon Armelle , Berry Martin , Hantaı̈ Daniel 
Published: April 2018

Because injury of the CNS causes an astrogliosis, characterized by cell swelling and proliferation, similar to the effects of the serine protease thrombin on astrocytes, we hypothesized that a high level of thrombin at the site of injury might initially induce an astrocyte reaction and later increase the expression of its specific inhibitor, thrombomodulin. Thrombomodulin could then stabilize the astroglial scar through its adhesive properties.Here, we studied thein vivoinjury response of astrocytes in the anterior medullary velum of adult rat by immunostaining andin situhybridization of thrombomodulin. Thrombomodulin was poorly expressed on astrocytes in normal tissue, increased up to 2 d after injury, and was still highly expressed at 6 d.To check that thrombin had a direct effect on thrombomodulin expression by astrocytes, we used brain cortical astrocyte primary cultures treated with either thrombin or the agonist peptide thrombin receptor-activating peptide-6, known to activate directly the thrombin G-protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR-1). Modification of thrombomodulin expression was studied by Western blotting and quantitative reverse transcription-PCR. There was a dose-dependent increase in thrombomodulin after 48 hr of treatment, with gene expression peaking at 24 hr but falling to control levels by 48 hr.Together, these results show the following: (1) injury increases astrocyte thrombomodulin expression; (2) thrombin might mediate thrombomodulin expression via the specific receptor PAR-1; and (3) serine proteases, their inhibitors, and the new family of GPCR, PARs, are active on astrogliosis.
Morphofunctional Plasticity in the Adult Hypothalamus Induces Regulation of Polysialic Acid–Neural Cell Adhesion Molecule through Changing Activity and Expression Levels of Polysialyltransferases
Authors: Soares Sylvia , von Boxberg Ysander , Ravaille-Veron Michèle , Vincent Jean-Didier , Nothias Fatiha 
Published: April 2018

Polysialic acid–neural cell adhesion molecule (PSA-NCAM) expression in the adult nervous system is restricted to regions retaining a capacity for morphological plasticity. For the female rat hypothalamoneurohypophysial system (HNS), we have previously shown that lactation induces a dramatic decrease in PSA-NCAM, while leaving the level of total NCAM protein unchanged. Here, we wanted to elucidate the molecular mechanisms leading to a downregulation of PSA, thereby stabilizing newly established synapses and neurohemal contacts that accompany the increased activity of oxytocinergic neurons.First, we show that the overall specific activity of polysialyltransferases present in tissue extracts from supraoptic nuclei decreases by ∼50% during lactation. So far, two polysialyltransferase enzymes, STX and PST, have been characterized for their capacity to transfer PSA onto NCAMin vitro. Using a competitive RT-PCR on RNA extracts from the HNS, we demonstrate furthermore a significant decrease in the expression levels of both STX and PST mRNAs in lactating versus virgin animals. Interestingly, this downregulation of NCAM polysialylation is not correlated with the post-transcriptional regulation of variable alternative spliced exon splicing, in contrast to neural development. The control of polysialylation via a regulation of both enzyme activity and expression underlines the important role of this post-translational modification of NCAM in morphofunctional plasticity in adult brain.
Dopamine Release and Uptake Dynamics within Nonhuman Primate StriatumIn Vitro
Authors: Cragg Stephanie J. , Hille Christopher J. , Greenfield Susan A. 
Published: April 2018

The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration ([DA]o) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrodein vitroin striatal sections from the common marmoset (Callithrix jacchus). [DA]oreleased by a single stimulus pulse varied threefold along a ventromedial–dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis–Menten kinetics, rate maximum,Vmax, varied with region: both [DA]oandVmaxwere greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. [DA]o,Vmax, and regional variation were two- to threefold greater than in rodent caudatoputamen.In addition, steady-state [DA]oat physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of [DA]oby these mechanisms differed significantly between limbic- and motor-associated domains.These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.
Bcl-XL–Caspase-9 Interactions in the Developing Nervous System: Evidence for Multiple Death Pathways
Authors: Zaidi Aliya U. , D'Sa-Eipper Cleta , Brenner Jennifer , Kuida Keisuke , Zheng Timothy S. , Flavell Richard A. , Rakic Pasko , Roth Kevin A. 
Published: April 2018

Programmed cell death is critical for normal nervous system development and is regulated by Bcl-2 and Caspase family members. Targeted disruption ofbcl-xL, an antiapoptoticbcl-2gene family member, causes massive death of immature neurons in the developing nervous system whereas disruption ofcaspase-9, a proapoptoticcaspasegene family member, leads to decreased neuronal apoptosis and neurodevelopmental abnormalities. To determine whether Bcl-XLand Caspase-9 interact in an obligate pathway of neuronal apoptosis,bcl-x/caspase-9double homozygous mutants were generated. The increased apoptosis of immature neurons observed in Bcl-XL-deficient embryos was completely prevented by concomitant Caspase-9 deficiency. In contrast,bcl-x−/−/caspase-9−/−embryonic mice exhibited an expanded ventricular zone and neuronal malformations identical to that observed in mice lacking only Caspase-9. These results indicate both epistatic and independent actions of Bcl-XLand Caspase-9 in neuronal programmed cell death.To examine Bcl-2 and Caspase family-dependent apoptotic pathways in telencephalic neurons, we compared the effects of cytosine arabinoside (AraC), a known neuronal apoptosis inducer, on wild-type, Bcl-XL-, Bax-, Caspase-9-, Caspase-3-, and p53-deficient telencephalic neuronsin vitro. AraC caused extensive apoptosis of wild-type and Bcl-XL-deficient neurons. p53- and Bax-deficient neurons showed marked protection from AraC-induced death, whereas Caspase-9- and Caspase-3-deficient neurons showed minimal or no protection, respectively. These findings contrast with our previous investigation of AraC-induced apoptosis of telencephalic neural precursor cells in which death was completely blocked by p53 or Caspase-9 deficiency but not Bax deficiency. In total, these results indicate a transition from Caspase-9- to Bax- and Bcl-XL-mediated neuronal apoptosis.
Hes1andHes5Activities Are Required for the Normal Development of the Hair Cells in the Mammalian Inner Ear
Authors: Zine Azel , Aubert Alexandre , Qiu Jiping , Therianos Stavros , Guillemot Francois , Kageyama Ryoichiro , de Ribaupierre Francois 
Published: April 2018

The mammalian inner ear contains two sensory organs, the cochlea and vestibule. Their sensory neuroepithelia are characterized by a mosaic of hair cells and supporting cells. Cochlear hair cells differentiate in four rows: a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs). Recent studies have shown that Math1, a mammalian homolog ofDrosophila atonalis a positive regulator of hair cell differentiation. The basic helix–loop–helix (bHLH) genesHes1andHes5(mammalianhairyandEnhancer-of-splithomologs) can influence cell fate determination by acting as negative regulators to inhibit the action of bHLH-positive regulators. We show by using reverse transcription-PCR analysis thatHes1,Hes5, andMath1are expressed in the developing mouse cochleae.In situhybridization revealed a widespread expression ofHes1in the greater epithelial ridge (GER) and in lesser epithelial ridge (LER) regions.Hes5is predominantly expressed in the LER, in supporting cells, and in a narrow band of cells within the GER.Examination of cochleae fromHes1−/−mice showed a significant increase in the number of IHCs, whereas cochleae fromHes5−/−mice showed a significant increase in the number of OHCs. In the vestibular system, targeted deletion ofHes1and to a lesser extentHes5lead to formation of supernumerary hair cells in the saccule and utricle.The supernumerary hair cells in the mutant mice showed an upregulation of Math1. These data indicate thatHes1andHes5participate together for the control of inner ear hair cell production, likely through the negative regulation of Math1.