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Journal of Neuroscience
Journal Prestige (SJR): 4.466
Citation Impact (citeScore): 6
Number of Followers: 316  
  Full-text available via subscription Subscription journal
ISSN (Print) 0270-6474 - ISSN (Online) 1529-2401
Published by Society for Neuroscience Homepage  [2 journals]
  • This Week in The Journal
    • Authors: Esch T.
      Pages: 9477 - 9477
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.twij.39.48.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Protein Kinase C and Calmodulin Serve As Calcium Sensors for
           Calcium-Stimulated Endocytosis at Synapses
    • Authors: Jin, Y.-H; Wu, X.-S, Shi, B, Zhang, Z, Guo, X, Gan, L, Chen, Z, Wu, L.-G.
      Pages: 9478 - 9490
      Abstract: Calcium influx triggers and facilitates endocytosis, which recycles vesicles and thus sustains synaptic transmission. Despite decades of studies, the underlying calcium sensor remained not well understood. Here, we examined two calcium binding proteins, protein kinase C (PKC) and calmodulin. Whether PKC is involved in endocytosis was unclear; whether calmodulin acts as a calcium sensor for endocytosis was neither clear, although calmodulin involvement in endocytosis had been suggested. We generated PKC (α or β-isoform) and calmodulin (calmodulin 2 gene) knock-out mice of either sex and measured endocytosis with capacitance measurements, pHluorin imaging and electron microscopy. We found that these knock-outs inhibited slow (~10–30 s) and rapid (
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0182-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • The LMTK1-TBC1D9B-Rab11A Cascade Regulates Dendritic Spine Formation via
           Endosome Trafficking
    • Authors: Nishino, H; Saito, T, Wei, R, Takano, T, Tsutsumi, K, Taniguchi, M, Ando, K, Tomomura, M, Fukuda, M, Hisanaga, S.-i.
      Pages: 9491 - 9502
      Abstract: Dendritic spines are postsynaptic protrusions at excitatory synapses that are critical for proper neuronal synaptic transmission. While lipid and protein membrane components are necessary for spine formation, it is largely unknown how they are recruited to developing spines. Endosomal trafficking is one mechanism that may influence this development. We recently reported that Lemur kinase 1A (LMTK1A), a membrane-bound Ser/Thr kinase, regulates trafficking of endosomes in neurons. LMTK1 has been shown to be a p35 Cdk5 activator-binding protein and a substrate for Cdk5-p35; however, its neuronal function has not been sufficiently studied. Here, we investigate the role of LMTK1 in spine formation. Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. Additionally, expression of kinase-negative LMTK1 stimulates spine formation in primary neurons and in vivo. LMTK1 controls spine formation through Rab11, a regulator of recycling endosome trafficking. We identify TBC1D9B, a Rab11A GTPase-activating protein (Rab11A GAP), as a LMTK1 binding protein, and find that TBC1D9B mediates LMTK1 activity on Rab11A. TBC1D9B inactivates Rab11A under the control of LMTK1A. Further, by analyzing the effect of decreased TBC1D9B expression in primary neurons, we demonstrate that TBC1D9B indeed regulates spine formation. This is the first demonstration of the biological function of TBC1D9B. Together, with the regulation of LMTK1 by Cdk5-p35, we propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel signaling mechanism regulating endosomal transport for synapse formation and function.SIGNIFICANCE STATEMENT Dendritic spines are postsynaptic specializations essential for synaptic transmission. However, it is not known how critical membrane components are recruited to spines for their formation. Endosomal trafficking is one such mechanism that may mediate this process. Here we investigate regulators of endosomal trafficking and their contribution to spine formation. We identify two novel factors, LMTK1 and TBC1D9B, which regulate spine formation upstream of Rab11A, a small GTPase. LMTK1 is a membrane bound Ser/Thr kinase regulated by Cdk5-p35, and TBC1D9B is a recently identified Rab11 GAP. LMTK1 controls the GAP activity of TBC1D9B on Rab11A, and TBC1D9B mediates the LMTK1 activity on Rab11A. We propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel mechanism controlling spine formation and function.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.3209-18.2019
      Issue No: Vol. 39, No. 48 (2019)
  • p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by
           Spheroid Rupture
    • Authors: Yong, Y; Gamage, K, Cheng, I, Barford, K, Spano, A, Winckler, B, Deppmann, C.
      Pages: 9503 - 9520
      Abstract: The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons derived from male and female neonatal mice maintain their structural integrity for ~18 h (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 h (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Before catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor-Rho-actin-dependent expansion of calcium-rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons are capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6, but not p75 neurotrophic factor receptor, is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occur toward the end of latency. Our results support the existence of an interaxonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.SIGNIFICANCE STATEMENT Developmental pruning shares several morphological similarities to both disease- and injury-induced degeneration, including spheroid formation. The function and underlying mechanisms governing axonal spheroid formation, however, remain unclear. In this study, we report that axons coordinate each other's degeneration during development via axonal spheroid rupture. Before irreversible breakdown of the axon in response to trophic withdrawal, p75 neurotrophic factor receptor-RhoA signaling governs the formation and growth of spheroids. These spheroids then rupture, allowing exchange of contents ≤10 kDa between the intracellular and extracellular space to drive death receptor 6 and calpain-dependent catastrophic degeneration. This finding informs not only our understanding of regressive events during development but may also provide a rationale for designing new treatments toward myriad neurodegenerative disorders.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1867-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Isolation of LMX1a Ventral Midbrain Progenitors Improves the Safety and
           Predictability of Human Pluripotent Stem Cell-Derived Neural Transplants
           in Parkinsonian Disease
    • Authors: de Luzy, I. R; Niclis, J. C, Gantner, C. W, Kauhausen, J. A, Hunt, C. P. J, Ermine, C, Pouton, C. W, Thompson, L. H, Parish, C. L.
      Pages: 9521 - 9531
      Abstract: Human pluripotent stem cells (hPSCs) are a promising resource for the replacement of degenerated ventral midbrain dopaminergic (vmDA) neurons in Parkinson's disease. Despite recent advances in protocols for the in vitro generation of vmDA neurons, the asynchronous and heterogeneous nature of the differentiations results in transplants of surprisingly low vmDA neuron purity. As the field advances toward the clinic, it will be optimal, if not essential, to remove poorly specified and potentially proliferative cells from donor preparations to ensure safety and predictable efficacy. Here, we use two novel hPSC knock-in reporter lines expressing GFP under the LMX1A and PITX3 promoters, to selectively isolate vm progenitors and DA precursors, respectively. For each cell line, unsorted, GFP+, and GFP– cells were transplanted into male or female Parkinsonian rodents. Only rats receiving unsorted cells, LMX1A-eGFP+, or PITX3-eGFP– cell grafts showed improved motor function over 6 months. Postmortem analysis revealed small grafts from PITX3-eGFP+ cells, suggesting that these DA precursors were not compatible with cell survival and integration. In contrast, LMX1A-eGFP+ grafts were highly enriched for vmDA neurons, and importantly excluded expansive proliferative populations and serotonergic neurons. These LMX1A-eGFP+ progenitor grafts accelerated behavioral recovery and innervated developmentally appropriate forebrain targets, whereas LMX1A-eGFP– cell grafts failed to restore motor deficits, supported by increased fiber growth into nondopaminergic target nuclei. This is the first study to use an hPSC-derived reporter line to purify vm progenitors, resulting in improved safety, predictability of the graft composition, and enhanced motor function.SIGNIFICANCE STATEMENT Clinical trials have shown functional integration of transplanted fetal-derived dopamine progenitors in Parkinson's disease. Human pluripotent stem cell (hPSC)-derived midbrain progenitors are now being tested as an alternative cell source; however, despite current differentiation protocols generating>80% correctly specified cells for implantation, resultant grafts contain a small fraction of dopamine neurons. Cell-sorting approaches, to select for correctly patterned cells before implantation, are being explored yet have been suboptimal to date. This study provides the first evidence of using 2 hPSC reporter lines (LMX1A-GFP and PITX3-GFP) to isolate correctly specified cells for transplantation. We show LMX1A-GFP+, but not PITX3-GFP+, cell grafts are more predictable, with smaller grafts, enriched in dopamine neurons, showing appropriate integration and accelerated functional recovery in Parkinsonian rats.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1160-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Estradiol Enhances the Depolarizing Response to GABA and AMPA Synaptic
           Conductances in Arcuate Kisspeptin Neurons by Diminishing Voltage-Gated
           Potassium Currents
    • Authors: DeFazio, R. A; Navarro, M. A, Adams, C. E, Milescu, L. S, Moenter, S. M.
      Pages: 9532 - 9545
      Abstract: Synaptic and intrinsic properties interact to sculpt neuronal output. Kisspeptin neurons in the hypothalamic arcuate nucleus help convey homeostatic estradiol feedback to central systems controlling fertility. Estradiol increases membrane depolarization induced by GABAA receptor activation in these neurons. We hypothesized that the mechanisms underlying estradiol-induced alterations in postsynaptic response to GABA, and also AMPA, receptor activation include regulation of voltage-gated potassium currents. Whole-cell recordings of arcuate kisspeptin neurons in brain slices from ovariectomized (OVX) and OVX+estradiol (OVX+E) female mice during estradiol negative feedback revealed that estradiol reduced capacitance, reduced transient and sustained potassium currents, and altered voltage dependence and kinetics of transient currents. Consistent with these observations, estradiol reduced rheobase and action potential latency. To study more directly interactions between synaptic and active intrinsic estradiol feedback targets, dynamic clamp was used to simulate GABA and AMPA conductances. Both GABA and AMPA dynamic clamp-induced postsynaptic potentials (PSPs) were smaller in neurons from OVX than OVX+E mice; blocking transient potassium currents eliminated this difference. To interrogate the role of the estradiol-induced changes in passive intrinsic properties, different Markov model structures based on the properties of the transient potassium current in cells from OVX or OVX+E mice were combined in silico with passive properties reflecting these two endocrine conditions. Some of tested models reproduced the effect on PSPs in silico, revealing that AMPA PSPs were more sensitive to changes in capacitance. These observations support the hypothesis that PSPs in arcuate kisspeptin neurons are regulated by estradiol-sensitive mechanisms including potassium conductances and membrane properties.SIGNIFICANCE STATEMENT Kisspeptin neurons relay estradiol feedback to gonadotropin-releasing hormone neurons, which regulate the reproductive system. The fast synaptic neurotransmitters GABA and glutamate rapidly depolarize arcuate kisspeptin neurons and estradiol increases this depolarization. Estradiol reduced both potassium current in the membrane potential range typically achieved during response to fast synaptic inputs and membrane capacitance. Using simulated GABA and glutamate synaptic inputs, we showed changes in both the passive and active intrinsic properties induced by in vivo estradiol treatment affect the response to synaptic inputs, with capacitance having a greater effect on response to glutamate. The suppression of both passive and active intrinsic properties by estradiol feedback thus renders arcuate kisspeptin neurons more sensitive to fast synaptic inputs.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0378-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Glutamatergic Neurons in the Piriform Cortex Influence the Activity of D1-
           and D2-Type Receptor-Expressing Olfactory Tubercle Neurons
    • Authors: White, K. A; Zhang, Y.-F, Zhang, Z, Bhattarai, J. P, Moberly, A. H, in 't Zandt, E. E, Pena-Bravo, J. I, Mi, H, Jia, X, Fuccillo, M. V, Xu, F, Ma, M, Wesson, D. W.
      Pages: 9546 - 9559
      Abstract: Sensory cortices process stimuli in manners essential for perception. Very little is known regarding interactions between olfactory cortices. The piriform "primary" olfactory cortex, especially its anterior division (aPCX), extends dense association fibers into the ventral striatum's olfactory tubercle (OT), yet whether this corticostriatal pathway is capable of shaping OT activity, including odor-evoked activity, is unknown. Further unresolved is the synaptic circuitry and the spatial localization of OT-innervating PCX neurons. Here we build upon standing literature to provide some answers to these questions through studies in mice of both sexes. First, we recorded the activity of OT neurons in awake mice while optically stimulating principal neurons in the aPCX and/or their association fibers in the OT while the mice were delivered odors. This uncovered evidence that PCX input indeed influences OT unit activity. We then used patch-clamp recordings and viral tracing to determine the connectivity of aPCX neurons upon OT neurons expressing dopamine receptor types D1 or D2, two prominent cell populations in the OT. These investigations uncovered that both populations of neurons receive monosynaptic inputs from aPCX glutamatergic neurons. Interestingly, this input originates largely from the ventrocaudal aPCX. These results shed light on some of the basic physiological properties of this pathway and the cell-types involved and provide a foundation for future studies to identify, among other things, whether this pathway has implications for perception.SIGNIFICANCE STATEMENT Sensory cortices interact to process stimuli in manners considered essential for perception. Very little is known regarding interactions between olfactory cortices. The present study sheds light on some of the basic physiological properties of a particular intercortical pathway in the olfactory system and provides a foundation for future studies to identify, among other things, whether this pathway has implications for perception.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1444-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Cochlear Efferent Innervation Is Sparse in Humans and Decreases with Age
    • Authors: Liberman, L. D; Liberman, M. C.
      Pages: 9560 - 9569
      Abstract: The mammalian cochlea is innervated by two cholinergic feedback systems called the medial olivocochlear (MOC) and lateral olivocochlear (LOC) pathways, which send control signals from the brainstem back to the outer hair cells and auditory-nerve fibers, respectively. Despite countless studies of the cochlear projections of these efferent fibers in animal models, comparable data for humans are almost completely lacking. Here, we immunostained the cochlear sensory epithelium from 23 normal-aging humans (14 males and 9 females), 0–86 years of age, with cholinergic markers to quantify the normal density of MOC and LOC projections, and the degree of age-related degeneration. In younger ears, the MOC density peaks in mid-cochlear regions and falls off both apically and basally, whereas the LOC innervation peaks near the apex. In older ears, MOC density decreases dramatically, whereas the LOC density does not. The loss of MOC feedback may contribute to the age-related decrease in word recognition in noise; however, even at its peak, the MOC density is lower than in other mammals, suggesting the MOC pathway is less important for human hearing.SIGNIFICANCE STATEMENT The cochlear epithelium and its sensory innervation are modulated by the olivocochlear (OC) efferent pathway. Although the medial OC (MOC) reflex has been extensively studied in humans, via contralateral sound suppression, the cochlear projections of these cholinergic neurons have not been described in humans. Here, we use immunostaining to quantify the MOC projections to outer hair cells and lateral OC (LOC) projections to the inner hair cell area in humans 0–89 years of age. We show age-related loss of MOC, but not LOC, innervation, which likely contributes to hearing impairments, and a relative paucity of MOC terminals at all ages, which may account for the relative weakness of the human MOC reflex and the difficulty in demonstrating a robust functional role in human experiments.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.3004-18.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Dentate Gyrus Mossy Cells Share a Role in Pattern Separation with Dentate
           Granule Cells and Proximal CA3 Pyramidal Cells
    • Authors: GoodSmith, D; Lee, H, Neunuebel, J. P, Song, H, Knierim, J. J.
      Pages: 9570 - 9584
      Abstract: The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and proximal CA3 (pCA3) regions have been implicated in pattern separation, in part through extracellular recording studies of these areas. However, the DG contains two types of excitatory cells: granule cells of the granule layer and mossy cells of the hilus. Little is known about the firing properties of mossy cells in freely moving animals, and it is unclear how their activity may contribute to the mnemonic functions of the hippocampus. Furthermore, tetrodes in the dentate granule layer and pCA3 pyramidal layer can also record mossy cells, thus introducing ambiguity into the identification of cell types recorded. Using a random forests classifier, we classified cells recorded in DG (Neunuebel and Knierim, 2014) and pCA3 (Lee et al., 2015) of 16 male rats and separately examined the responses of granule cells, mossy cells, and pCA3 pyramidal cells in a local/global cue mismatch task. All three cell types displayed low correlations between the population representations of the rat's position in the standard and cue-mismatch sessions. These results suggest that all three excitatory cell types within the DG/pCA3 circuit may act as a single functional unit to support pattern separation.SIGNIFICANCE STATEMENT Mossy cells in the dentate gyrus (DG) are an integral component of the DG/pCA3 circuit. While the role of granule cells in the circuitry and computations of the hippocampus has been a focus of study for decades, the contributions of mossy cells have been largely overlooked. Recent studies have revealed the spatial firing properties of mossy cells in awake behaving animals, but how the activity of these highly active cells contributes to the mnemonic functions of the DG is uncertain. We separately analyzed mossy cells, granule cells, and pCA3 cells and found that all three cell types respond similarly to a local/global cue mismatch, suggesting that they form a single functional unit supporting pattern separation.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0940-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Multivariate Analysis of Electrophysiological Signals Reveals the Temporal
           Properties of Visuomotor Computations for Precision Grips
    • Authors: Guo, L. L; Nestor, A, Nemrodov, D, Frost, A, Niemeier, M.
      Pages: 9585 - 9597
      Abstract: The frontoparietal networks underlying grasping movements have been extensively studied, especially using fMRI. Accordingly, whereas much is known about their cortical locus much less is known about the temporal dynamics of visuomotor transformations. Here, we show that multivariate EEG analysis allows for detailed insights into the time course of visual and visuomotor computations of precision grasps. Male and female human participants first previewed one of several objects and, upon its reappearance, reached to grasp it with the thumb and index finger along one of its two symmetry axes. Object shape classifiers reached transient accuracies of 70% at ~105 ms, especially based on scalp sites over visual cortex, dropping to lower levels thereafter. Grasp orientation classifiers relied on a system of occipital-to-frontal electrodes. Their accuracy rose concurrently with shape classification but ramped up more gradually, and the slope of the classification curve predicted individual reaction times. Further, cross-temporal generalization revealed that dynamic shape representation involved early and late neural generators that reactivated one another. In contrast, grasp computations involved a chain of generators attaining a sustained state about 100 ms before movement onset. Our results reveal the progression of visual and visuomotor representations over the course of planning and executing grasp movements.SIGNIFICANCE STATEMENT Grasping an object requires the brain to perform visual-to-motor transformations of the object's properties. Although much of the neuroanatomic basis of visuomotor transformations has been uncovered, little is known about its time course. Here, we orthogonally manipulated object visual characteristics and grasp orientation, and used multivariate EEG analysis to reveal that visual and visuomotor computations follow similar time courses but display different properties and dynamics.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0914-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of
           G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine
           Density and Enhance Memory Consolidation
    • Authors: Kim, J; Schalk, J. C, Koss, W. A, Gremminger, R. L, Taxier, L. R, Gross, K. S, Frick, K. M.
      Pages: 9598 - 9610
      Abstract: Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17β-estradiol (E2) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E2-induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice.SIGNIFICANCE STATEMENT Emerging evidence suggests that G-protein-coupled estrogen receptor (GPER) activation mimics effects of 17β-estradiol on hippocampal memory consolidation. Unlike canonical estrogen receptors, GPER activation is associated with reduced cancer cell proliferation; thus, understanding the molecular mechanisms through which GPER regulates hippocampal function may provide new avenues for the development of drugs that provide the cognitive benefits of estrogens without harmful side effects. Here, we demonstrate that GPER increases CA1 dendritic spine density and hippocampal memory consolidation in a manner dependent on actin polymerization and c-Jun N-terminal kinase phosphorylation. These findings provide novel insights into the role of GPER in mediating hippocampal morphology and memory consolidation, and may suggest first steps toward new therapeutics that more safely and effectively reduce memory decline in menopausal women.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.2687-18.2019
      Issue No: Vol. 39, No. 48 (2019)
  • ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
    • Authors: Rawat, V; Wang, S, Sima, J, Bar, R, Liraz, O, Gundimeda, U, Parekh, T, Chan, J, Johansson, J. O, Tang, C, Chui, H. C, Harrington, M. G, Michaelson, D. M, Yassine, H. N.
      Pages: 9611 - 9622
      Abstract: The APOE 4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid (Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from APOE 4/4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE 3/3 carriers. Enhancing ABCA1 activity rescued impaired Aβ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1400-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Tau Misfolding Efficiently Propagates between Individual Intact
           Hippocampal Neurons
    • Authors: Hallinan, G. I; Vargas-Caballero, M, West, J, Deinhardt, K.
      Pages: 9623 - 9632
      Abstract: Neurofibrillary tangles, formed of misfolded, hyperphosphorylated tau protein, are a pathological hallmark of several neurodegenerations, including Alzheimer's disease. Tau pathology spreads between neurons and propagates misfolding in a prion-like manner throughout connected neuronal circuits. Tauopathy is accompanied by significant neuronal death, but the relationships between initial tau misfolding, propagation across connected neurons and cytotoxicity remain unclear. In particular the immediate functional consequence of tau misfolding for the individual neuron is not well understood. Here, using microfluidic devices to recreate discretely organized neuronal connections, we show that the spread and propagation of misfolded tau between individual murine neurons is rapid and efficient; it occurs within days. The neurons containing and propagating tau pathology display selective axonal transport deficits but remain viable and electrically competent. Therefore, we demonstrate that seed-competent misfolded tau species do not acutely cause cell death, but instead initiate discrete cellular dysfunctions.SIGNIFICANCE STATEMENT Public awareness of progressive neurodegenerations such as dementias associated with aging or repetitive head trauma is rising. Protein misfolding underlies many neurodegenerative diseases including tauopathies, where the misfolded tau protein propagates pathology through connected brain circuits in a prion-like manner. Clinically, these diseases progress over the course of years. Here we show that the underlying protein misfolding propagates rapidly between individual neurons. Presence of misfolded tau is not directly cytotoxic to the neuron; the cells remain viable with limited deficits. This suggests that neurons with tau pathology could be rescued with a therapeutic disease modifier and highlights an under-appreciated time window for such therapeutic intervention.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1590-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Apnea Associated with Brainstem Seizures in Cacna1aS218L Mice Is Caused by
           Medullary Spreading Depolarization
    • Authors: Jansen, N. A; Schenke, M, Voskuyl, R. A, Thijs, R. D, van den Maagdenberg, A. M. J. M, Tolner, E. A.
      Pages: 9633 - 9644
      Abstract: Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated CaV2.1 Ca2+ channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of nonfatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than vice versa. Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea.SIGNIFICANCE STATEMENT Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during nonfatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.1713-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against
           Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's
    • Authors: Lei, M; Teo, J. D, Song, H, McEwen, H. P, Yup Lee, J, Couttas, T. A, Duncan, T, Chesworth, R, Bertz, J, Przybyla, M, Van Eersel, J, Heng, B, Guillemin, G. J, Ittner, L. M, Fath, T, Garner, B, Ittner, A, Karl, T, Don, A. S.
      Pages: 9645 - 9659
      Abstract: Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippocampal S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid β (Aβ) formation from amyloid precursor protein (APP) in vitro. To determine whether loss of S1P sensitizes to Aβ-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APPSwInd) mice. SK2 deficiency greatly reduced Aβ content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippocampal electroencephalography. However, several key measures of APPSwInd-dependent neurodegeneration were enhanced on the SK2-null background, despite reduced Aβ burden. These included hippocampal volume loss, oligodendrocyte attrition and myelin loss, and impaired performance in Y-maze and social novelty memory tests. Inhibition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glial cells, linking loss of SK2 activity and S1P in AD to perturbed endosomal lipid metabolism. Our findings establish SK2 as an important endogenous regulator of both APP processing to Aβ, and oligodendrocyte survival, in vivo. These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD.SIGNIFICANCE STATEMENT Genetic, neuropathological, and functional studies implicate both Aβ and altered lipid metabolism and/or signaling as key pathogenic drivers of Alzheimer's disease. In this study, we first demonstrate that the enzyme SK2, which generates the signaling lipid S1P, is required for Aβ formation from APP in vivo. Second, we establish a new role for SK2 in the protection of oligodendrocytes and myelin. Loss of SK2 sensitizes to Aβ-mediated neurodegeneration by attenuating oligodendrocyte survival and promoting hippocampal atrophy, despite reduced Aβ burden. Our findings support a model in which Aβ-independent sensitizing influences such as loss of neuroprotective S1P are more important drivers of neurodegeneration than gross Aβ concentration or plaque density.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0524-19.2019
      Issue No: Vol. 39, No. 48 (2019)
  • Altered Recruitment of Motor Cortex Neuronal Activity During the Grasping
           Phase of Skilled Reaching in a Chronic Rat Model of Unilateral
    • Authors: Hyland, B. I; Seeger-Armbruster, S, Smither, R. A, Parr-Brownlie, L. C.
      Pages: 9660 - 9672
      Abstract: Parkinson's disease causes prominent difficulties in the generation and execution of voluntary limb movements, including regulation of distal muscles and coordination of proximal and distal movement components to achieve accurate grasping. Difficulties with manual dexterity have a major impact on activities of daily living. We used extracellular single neuron recordings to investigate the neural underpinnings of parkinsonian movement deficits in the motor cortex of chronic unilateral 6-hydroxydopamine lesion male rats performing a skilled reach-to-grasp task the. Both normal movements and parkinsonian deficits in this task have striking homology to human performance. In lesioned animals there were several differences in the activity of cortical neurons during reaches by the affected limb compared with control rats. These included an increase in proportions of neurons showing rate decreases, along with increased amplitude of their average rate-decrease response at specific times during the reach, suggesting a shift in the balance of net excitation and inhibition of cortical neurons; a significant increase in the duration of rate-increase responses, which could result from reduced coupling of cortical activity to specific movement components; and changes in the timing and incidence of neurons with pure rate-increase or biphasic responses, particularly at the end of reach when grasping would normally be occurring. The changes in cortical activity may account for the deficits that occur in skilled distal motor control following dopamine depletion, and highlight the need for treatment strategies targeted toward modulating cortical mechanisms for fine distal motor control in patients.SIGNIFICANCE STATEMENT We show for the first time in a chronic lesion rat model of Parkinson's disease movement deficits that there are specific changes in motor cortex neuron activity associated with the grasping phase of a skilled motor task. Such changes provide a possible mechanism underpinning the problems with manual dexterity seen in Parkinson's patients and highlight the need for treatment strategies targeted toward distal motor control.
      PubDate: 2019-11-27T09:30:26-08:00
      DOI: 10.1523/JNEUROSCI.0720-19.2019
      Issue No: Vol. 39, No. 48 (2019)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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