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Journal Cover Journal of Neuroscience
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   ISSN (Print) 0270-6474 - ISSN (Online) 1529-2401
   Published by Society for Neuroscience Homepage  [2 journals]
  • This Week in The Journal
    • PubDate: 2017-10-11T08:41:41-07:00
      Issue No: Vol. 37, No. 41 (2017)
  • Parkinson's Disease Is Not Simply a Prion Disorder
    • Authors: Surmeier, D. J; Obeso, J. A, Halliday, G. M.
      Pages: 9799 - 9807
      Abstract: The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD.Dual Perspectives Companion Paper: Prying into the Prion Hypothesis for Parkinson's Disease, by Patrik Brundin and Ronald Melki
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.1787-16.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Prying into the Prion Hypothesis for Parkinson's Disease
    • Authors: Brundin, P; Melki, R.
      Pages: 9808 - 9818
      Abstract: In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future.Dual Perspectives Companion Paper: Parkinson's Disease Is Not Simply a Prion Disorder, by D. James Surmeier, José A. Obeso, and Glenda M. Halliday
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.1788-16.2017
      Issue No: Vol. 37, No. 41 (2017)
  • T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice
    • Authors: Rosen, S. F; Ham, B, Drouin, S, Boachie, N, Chabot-Dore, A.-J, Austin, J.-S, Diatchenko, L, Mogil, J. S.
      Pages: 9819 - 9827
      Abstract: It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of -opioid receptors. We also observe that T-cell-deficient (nude and Rag1-null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4+ or CD8+ T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy.SIGNIFICANCE STATEMENT Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), -opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.2053-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as
           a Synaptic Adhesion Molecule that Promotes Synapse Formation
    • Authors: Jiang, W; Wei, M, Liu, M, Pan, Y, Cao, D, Yang, X, Zhang, C.
      Pages: 9828 - 9843
      Abstract: The proper formation of synapses—specialized unitary structures formed between two neurons—is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0729-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis
           Entry into Central Neurons
    • Authors: Kennedy, T; Broadie, K.
      Pages: 9844 - 9858
      Abstract: Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0723-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Astrocyte-Mediated Neuronal Synchronization Properties Revealed by False
           Gliotransmitter Release
    • Authors: Pirttimaki, T. M; Sims, R. E, Saunders, G, Antonio, S. A, Codadu, N. K, Parri, H. R.
      Pages: 9859 - 9870
      Abstract: Astrocytes spontaneously release glutamate (Glut) as a gliotransmitter (GT), resulting in the generation of extrasynaptic NMDAR-mediated slow inward currents (SICs) in neighboring neurons, which can increase local neuronal excitability. However, there is a deficit in our knowledge of the factors that control spontaneous astrocyte GT release and the extent of its influence. We found that, in rat brain slices, increasing the supply of the physiological transmitter Glut increased the frequency and signaling charge of SICs over an extended period. This phenomenon was replicated by exogenous preexposure to the amino acid D-aspartate (D-Asp). Using D-Asp as a "false" GT, we determined the extent of local neuron excitation by GT release in ventrobasal thalamus, CA1 hippocampus, and somatosensory cortex. By analyzing synchronized neuronal NMDAR-mediated excitation, we found that the properties of the excitation were conserved in different brain areas. In the three areas, astrocyte-derived GT release synchronized groups of neurons at distances of >;200 μm. Individual neurons participated in more than one synchronized population, indicating that individual neurons can be excited by more than one astrocyte and that individual astrocytes may determine a neuron's synchronized network. The results confirm that astrocytes can act as excitatory nodes that can influence neurons over a significant range in a number of brain regions. Our findings further suggest that chronic elevation of ambient Glut levels can lead to increased GT Glut release, which may be relevant in some pathological states.SIGNIFICANCE STATEMENT Astrocytes spontaneously release glutamate (Glut) and other gliotransmitters (GTs) that can modify neuronal activity. Exposing brain slices to Glut and D-aspartate (D-Asp) before recording resulted in an increase in frequency of GT-mediated astrocyte–neuron signaling. Using D-Asp, it was possible to investigate the effects of specific GT release at neuronal NMDARs. Calcium imaging showed synchronized activity in groups of neurons in cortex, hippocampus, and thalamus. The size of these populations was similar in all areas and some neurons were involved in more than one synchronous group. The findings show that GT release is supply dependent and that the properties of the signaling and activated networks are largely conserved between different brain areas.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.2761-16.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Visual Responses in FEF, Unlike V1, Primarily Reflect When the Visual
           Context Renders a Receptive Field Salient
    • Authors: Joiner, W. M; Cavanaugh, J, Wurtz, R. H, Cumming, B. G.
      Pages: 9871 - 9879
      Abstract: When light falls within a neuronal visual receptive field (RF) the resulting activity is referred to as the visual response. Recent work suggests this activity is in response to both the visual stimulation and the abrupt appearance, or salience, of the presentation. Here we present a novel method for distinguishing the two, based on the timing of random and nonrandom presentations. We examined these contributions in frontal eye field (FEF; N = 51) and as a comparison, an early stage in the primary visual cortex (V1; N = 15) of male monkeys (Macaca mulatta). An array of identical stimuli was presented within and outside the neuronal RF while we manipulated salience by varying the time between stimulus presentations. We hypothesized that the rapid presentation would reduce salience (the sudden appearance within the visual field) of a stimulus at any one location, and thus decrease responses driven by salience in the RF. We found that when the interstimulus interval decreased from 500 to 16 ms there was an approximate 79% reduction in the FEF response compared with an estimated 17% decrease in V1. This reduction in FEF response for rapid presentation was evident even when the random sequence preceding a stimulus did not stimulate the RF for 500 ms. The time course of these response changes in FEF suggest that salience is represented much earlier (
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.1446-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in
           Mouse Models of Down Syndrome
    • Authors: William, C. M; Saqran, L, Stern, M. A, Chiang, C. L, Herrick, S. P, Rangwala, A, Albers, M. W, Frosch, M. P, Hyman, B. T.
      Pages: 9880 - 9888
      Abstract: Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivo.SIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo. This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.1045-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • The TRPM1 Channel Is Required for Development of the Rod ON Bipolar
           Cell-AII Amacrine Cell Pathway in the Retinal Circuit
    • Authors: Kozuka, T; Chaya, T, Tamalu, F, Shimada, M, Fujimaki-Aoba, K, Kuwahara, R, Watanabe, S.-I, Furukawa, T.
      Pages: 9889 - 9900
      Abstract: Neurotransmission plays an essential role in neural circuit formation in the central nervous system (CNS). Although neurotransmission has been recently clarified as a key modulator of retinal circuit development, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we investigated the role of neurotransmission from photoreceptor cells to ON bipolar cells in development using mutant mouse lines of both sexes in which this transmission is abrogated. We found that deletion of the ON bipolar cation channel TRPM1 results in the abnormal contraction of rod bipolar terminals and a decreased number of their synaptic connections with amacrine cells. In contrast, these histological alterations were not caused by a disruption of total glutamate transmission due to loss of the ON bipolar glutamate receptor mGluR6 or the photoreceptor glutamate transporter VGluT1. In addition, TRPM1 deficiency led to the reduction of total dendritic length, branch numbers, and cell body size in AII amacrine cells. Activated Goα, known to close the TRPM1 channel, interacted with TRPM1 and induced the contraction of rod bipolar terminals. Furthermore, overexpression of Channelrhodopsin-2 partially rescued rod bipolar cell development in the TRPM1–/– retina, whereas the rescue effect by a constitutively closed form of TRPM1 was lower than that by the native form. Our results suggest that TRPM1 channel opening is essential for rod bipolar pathway establishment in development.SIGNIFICANCE STATEMENT Neurotransmission has been recognized recently as a key modulator of retinal circuit development in the CNS. However, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we focused on neurotransmission between rod photoreceptor cells and rod bipolar cells in the retina. We used genetically modified mouse models which abrogate each step of neurotransmission: presynaptic glutamate release, postsynaptic glutamate reception, or transduction channel function. We found that the TRPM1 transduction channel is required for the development of rod bipolar cells and their synaptic formation with subsequent neurons, independently of glutamate transmission. This study advances our understanding of neurotransmission-mediated retinal circuit refinement.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0824-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Regional Cellular Environment Shapes Phenotypic Variations of Hippocampal
           and Neocortical Chandelier Cells
    • Authors: Ishino, Y; Yetman, M. J, Sossi, S. M, Steinecke, A, Hayano, Y, Taniguchi, H.
      Pages: 9901 - 9916
      Abstract: Different cortical regions processing distinct information, such as the hippocampus and the neocortex, share common cellular components and circuit motifs but form unique networks by modifying these cardinal units. Cortical circuits include diverse types of GABAergic interneurons (INs) that shape activity of excitatory principal neurons (PNs). Canonical IN types conserved across distinct cortical regions have been defined by their morphological, electrophysiological, and neurochemical properties. However, it remains largely unknown whether canonical IN types undergo specific modifications in distinct cortical regions and display "regional variants." It is also poorly understood whether such phenotypic variations are shaped by early specification or regional cellular environment. The chandelier cell (ChC) is a highly stereotyped IN type that innervates axon initial segments of PNs and thus serves as a good model with which to address this issue. Here, we show that Cadherin-6 (Cdh6), a homophilic cell adhesion molecule, is a reliable marker of ChCs and Cdh6-CreER mice (both sexes) provide genetic access to hippocampal ChCs (h-ChCs). We demonstrate that, compared with neocortical ChCs (nc-ChCs), h-ChCs cover twice as much area and innervate twice as many PNs. Interestingly, a subclass of h-ChCs exhibits calretinin (CR) expression, which is not found in nc-ChCs. Furthermore, we find that h-ChCs appear to be born earlier than nc-ChCs. Surprisingly, despite the difference in temporal origins, ChCs display host-region-dependent axonal/synaptic organization and CR expression when transplanted heterotopically. These results suggest that local cellular environment plays a critical role in shaping terminal phenotypes of regional IN variants in the hippocampus and the neocortex.SIGNIFICANCE STATEMENT Canonical interneuron (IN) types conserved across distinct cortical regions such as the hippocampus and the neocortex are defined by morphology, physiology, and gene expression. However, it remains unknown whether they display phenotypic variations in different cortical regions. In addition, it is unclear whether terminal phenotypes of regional IN variants belonging to a canonical IN type are determined intrinsically or extrinsically. Our results provide evidence of striking differences in axonal/synaptic organization and calretinin expression between hippocampal chandelier cells (ChCs) and neocortical ChCs. They also reveal that local cellular environment in distinct cortical regions regulates these terminal phenotypes. Therefore, our study suggests that local cortical environment shapes the phenotypes of regional IN variants, which may be required for unique circuit operations in distinct cortical regions.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0047-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of
           Frontotemporal Dementia
    • Authors: Seo, J; Kritskiy, O, Watson, L. A, Barker, S. J, Dey, D, Raja, W. K, Lin, Y.-T, Ko, T, Cho, S, Penney, J, Silva, M. C, Sheridan, S. D, Lucente, D, Gusella, J. F, Dickerson, B. C, Haggarty, S. J, Tsai, L.-H.
      Pages: 9917 - 9924
      Abstract: Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (p35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with p35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:p35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aβ accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the p35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant p35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0621-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of
           Protein Kinase A: Implications for Multiple Sclerosis
    • Authors: Qin, J; Sikkema, A. H, van der Bij, K, de Jonge, J. C, Klappe, K, Nies, V, Jonker, J. W, Kok, J. W, Hoekstra, D, Baron, W.
      Pages: 9925 - 9938
      Abstract: Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids with a potential to modulate signaling pathways) could counteract fibronectin-mediated inhibition of OPC maturation. Exclusive exposure of rat oligodendrocytes to GD1a, but not other gangliosides, overcomes aggregated fibronectin-induced inhibition of myelin membrane formation, in vitro, and OPC differentiation in fibronectin aggregate containing cuprizone-induced demyelinated lesions in male mice. GD1a exerts its effect on OPCs by inducing their proliferation and, at a late stage, by modulating OPC maturation. Kinase activity profiling revealed that GD1a activated a protein kinase A (PKA)-dependent signaling pathway and increased phosphorylation of the transcription factor cAMP response element-binding protein. Consistently, the effect of GD1a in restoring myelin membrane formation in the presence of fibronectin aggregates was abolished by the PKA inhibitor H89, whereas the effect of GD1a was mimicked by the PKA activator dibutyryl-cAMP. Together, GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation by activating a PKA-dependent signaling pathway. Given the persistent presence of fibronectin aggregates in MS lesions, ganglioside GD1a might act as a potential novel therapeutic tool to selectively modulate the detrimental signaling environment that precludes remyelination.SIGNIFICANCE STATEMENT As an environmental factor, aggregates of the extracellular matrix protein fibronectin perturb the maturation of oligodendrocyte progenitor cells (OPCs), thereby impeding remyelination, in the demyelinating disease multiple sclerosis (MS). Here we demonstrate that exogenous addition of ganglioside GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation, both in vitro and in vivo, by activating a PKA-dependent signaling pathway. We propose that targeted delivery of GD1a to MS lesions may act as a potential novel molecular tool to boost maturation of resident OPCs to overcome remyelination failure and halt disease progression.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0103-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Oscillatory Reinstatement Enhances Declarative Memory
    • Authors: Javadi, A.-H; Glen, J. C, Halkiopoulos, S, Schulz, M, Spiers, H. J.
      Pages: 9939 - 9944
      Abstract: Declarative memory recall is thought to involve the reinstatement of neural activity patterns that occurred previously during encoding. Consistent with this view, greater similarity between patterns of activity recorded during encoding and retrieval has been found to predict better memory performance in a number of studies. Recent models have argued that neural oscillations may be crucial to reinstatement for successful memory retrieval. However, to date, no causal evidence has been provided to support this theory, nor has the impact of oscillatory electrical brain stimulation during encoding and retrieval been assessed. To explore this we used transcranial alternating current stimulation over the left dorsolateral prefrontal cortex of human participants [n = 70, 45 females; age mean (SD) = 22.12 (2.16)] during a declarative memory task. Participants received either the same frequency during encoding and retrieval (60–60 or 90–90 Hz) or different frequencies (60–90 or 90–60 Hz). When frequencies matched there was a significant memory improvement (at both 60 and 90 Hz) relative to sham stimulation. No improvement occurred when frequencies mismatched. Our results provide support for the role of oscillatory reinstatement in memory retrieval.SIGNIFICANCE STATEMENT Recent neurobiological models of memory have argued that large-scale neural oscillations are reinstated to support successful memory retrieval. Here we used transcranial alternating current stimulation (tACS) to test these models. tACS has recently been shown to induce neural oscillations at the frequency stimulated. We stimulated over the left dorsolateral prefrontal cortex during a declarative memory task involving learning a set of words. We found that tACS applied at the same frequency during encoding and retrieval enhances memory. We also find no difference between the two applied frequencies. Thus our results are consistent with the proposal that reinstatement of neural oscillations during retrieval supports successful memory retrieval.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0265-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor
           Intracellular Trapping
    • Authors: Palenzuela, R; Gutierrez, Y, Draffin, J. E, Lario, A, Benoist, M, Esteban, J. A.
      Pages: 9945 - 9963
      Abstract: The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR-mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission.SIGNIFICANCE STATEMENT The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0505-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Sodium Dynamics in Pyramidal Neuron Dendritic Spines: Synaptically Evoked
           Entry Predominantly through AMPA Receptors and Removal by Diffusion
    • Authors: Miyazaki, K; Ross, W. N.
      Pages: 9964 - 9976
      Abstract: Dendritic spines are key elements underlying synaptic integration and cellular plasticity, but many features of these important structures are not known or are controversial. We examined these properties using newly developed simultaneous sodium and calcium imaging with single-spine resolution in pyramidal neurons in rat hippocampal slices from either sex. Indicators for both ions were loaded through the somatic patch pipette, which also recorded electrical responses. Fluorescence changes were detected with a high-speed, low-noise CCD camera. Following subthreshold electrical stimulation, postsynaptic sodium entry is almost entirely through AMPA receptors with little contribution from entry through NMDA receptors or voltage-gated sodium channels. Sodium removal from the spine head is through rapid diffusion out to the dendrite through the spine neck with a half-removal time of ~16 ms, which suggests the neck has low resistance. Peak [Na+]i changes during single EPSPs are ~5 mm. Stronger electrical stimulation evoked small plateau potentials that had significant longer-lasting localized [Na+]i increases mediated through NMDA receptors.SIGNIFICANCE STATEMENT Dendritic spines, small structures that are difficult to investigate, are important elements in the fundamental processes of synaptic integration and plasticity. The main tool for examining these structures has been calcium imaging. However, the kinds of information that calcium imaging reveals is limited. We used newly developed, high-speed, simultaneous sodium and calcium imaging to examine ion dynamics in spines in hippocampal pyramidal neurons. We found that following single subthreshold synaptic activation most sodium entry was through AMPA receptors and not through NMDA receptors or through voltage-gated sodium channels and that the spine neck is not a significant resistance barrier. Most spine mechanisms are linear. However, regenerative NMDA conductances can be activated with stronger stimulation.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.1758-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • A Population of Indirect Pathway Striatal Projection Neurons Is
           Selectively Entrained to Parkinsonian Beta Oscillations
    • Authors: Sharott, A; Vinciati, F, Nakamura, K. C, Magill, P. J.
      Pages: 9977 - 9998
      Abstract: Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical–basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (~1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15–30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits.SIGNIFICANCE STATEMENT Chronic depletion of dopamine from the striatum, a part of the basal ganglia, causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters striatal neuron firing in vivo, with an emphasis on defining whether and how spiny projection neurons (SPNs) engage in the synchronized beta-frequency (15–30 Hz) oscillations that become pathologically exaggerated throughout basal ganglia circuits in parkinsonism. We discovered that a select population of so-called "indirect pathway" SPNs not only fire at abnormally high rates, but are also particularly prone to being recruited to exaggerated beta oscillations. Our results provide an important link between two complementary theories that explain the presentation of disease symptoms on the basis of changes in firing rate or firing synchronization/rhythmicity.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0658-17.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Domain-General Brain Regions Do Not Track Linguistic Input as Closely as
           Language-Selective Regions
    • Authors: Blank, I. A; Fedorenko, E.
      Pages: 9999 - 10011
      Abstract: Language comprehension engages a cortical network of left frontal and temporal regions. Activity in this network is language-selective, showing virtually no modulation by nonlinguistic tasks. In addition, language comprehension engages a second network consisting of bilateral frontal, parietal, cingulate, and insular regions. Activity in this "multiple demand" (MD) network scales with comprehension difficulty, but also with cognitive effort across a wide range of nonlinguistic tasks in a domain-general fashion. Given the functional dissociation between the language and MD networks, their respective contributions to comprehension are likely distinct, yet such differences remain elusive. Prior neuroimaging studies have suggested that activity in each network covaries with some linguistic features that, behaviorally, influence on-line processing and comprehension. This sensitivity of the language and MD networks to local input characteristics has often been interpreted, implicitly or explicitly, as evidence that both networks track linguistic input closely, and in a manner consistent across individuals. Here, we used fMRI to directly test this assumption by comparing the BOLD signal time courses in each network across different people (n = 45, men and women) listening to the same story. Language network activity showed fewer individual differences, indicative of closer input tracking, whereas MD network activity was more idiosyncratic and, moreover, showed lower reliability within an individual across repetitions of a story. These findings constrain cognitive models of language comprehension by suggesting a novel distinction between the processes implemented in the language and MD networks.SIGNIFICANCE STATEMENT Language comprehension recruits both language-specific mechanisms and domain-general mechanisms that are engaged in many cognitive processes. In the human cortex, language-selective mechanisms are implemented in the left-lateralized "core language network", whereas domain-general mechanisms are implemented in the bilateral "multiple demand" (MD) network. Here, we report the first direct comparison of the respective contributions of these networks to naturalistic story comprehension. Using a novel combination of neuroimaging approaches we find that MD regions track stories less closely than language regions. This finding constrains the possible contributions of the MD network to comprehension, contrasts with accounts positing that this network has continuous access to linguistic input, and suggests a new typology of comprehension processes based on their extent of input tracking.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.3642-16.2017
      Issue No: Vol. 37, No. 41 (2017)
  • Adaptation of Thalamic Neurons Provides Information about the
           Spatiotemporal Context of Stimulus History
    • Authors: Liu, C; Foffani, G, Scaglione, A, Aguilar, J, Moxon, K. A.
      Pages: 10012 - 10021
      Abstract: Adaptation of neural responses due to the history of sensory input has been observed across all sensory modalities. However, the computational role of adaptation is not fully understood, especially when one considers neural coding problems in which adaptation increases the ambiguity of the neural responses to simple stimuli. To address this, we quantified the impact of adaptation on the information conveyed by thalamic neurons about paired whisker stimuli in male rat. At the single neuron level, although paired-pulse adaptation reduces the information about the present stimulus, the information per spike increases. Moreover, the adapted response can convey significant amounts of information about whether, when and where a previous stimulus occurred. At the population level, ambiguity of the adapted responses about the present stimulus can be compensated for by large numbers of neurons. Therefore, paired-pulse adaptation does not reduce the discriminability of simple stimuli. It provides information about the spatiotemporal context of stimulus history.SIGNIFICANCE STATEMENT The present work provides a computational framework that demonstrates how adaptation allows neurons to encode spatiotemporal dynamics of stimulus history.
      PubDate: 2017-10-11T08:41:41-07:00
      DOI: 10.1523/JNEUROSCI.0637-17.2017
      Issue No: Vol. 37, No. 41 (2017)
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