Wednesday, March 9, 2011

Hot off the presses! Mar 10 Neuron

The Mar 10 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • All the Embryo's a Stage, and Olig2 in Its Time Plays Many Parts
    - Neuron (Cambridge Mass ) 69(5):833-835 (2011)
    Olig2 is essential for the selection of motor neuron and oligodendrocyte fates and the choice of neural progenitors to either proliferate or differentiate. Three new studies demonstrate that these diverse actions of Olig2 are gated by phosphorylation at two distinct motifs and that Olig2's proliferative function acts in opposition to the p53 tumor suppressor pathway.
  • A Cytokine-Dependent Switch for Glial-Neuron Interactions
    - Neuron (Cambridge Mass ) 69(5):835-837 (2011)
    Though transmitters can be released from astrocytes, the conditions that permit their modulation of synaptic transmission are under debate. Santello et al. in this issue of Neuron now show that TNFα promotes a burst mode of glial transmitter release that escapes reuptake processes allowing access to neuronal NMDA receptors.
  • Understanding the Risky Business of Adolescence
    - Neuron (Cambridge Mass ) 69(5):837-839 (2011)
    Heightened sensitivity to emotional faces may contribute to less risk taking and susceptibility to peer influence in adolescents. A longitudinal study from Pfeifer et al. reveals a developmental increase in ventral striatum activity in early adolescence in response to emotional faces, which correlates with improved measures of resistance to peer influence and risky behavior.
  • Notch in the Vertebrate Nervous System: An Old Dog with New Tricks
    - Neuron (Cambridge Mass ) 69(5):840-855 (2011)
    The Notch pathway is prominent among those known to regulate neural development in vertebrates. Notch receptor activation can inhibit neurogenesis, maintain neural progenitor character, and in some contexts promote gliogenesis and drive binary fate choices. Recently, a wave of exciting studies has emerged, which has both solidified previously held assertions and expanded our understanding of Notch function during neurogenesis and in the adult brain. These studies have examined pathway regulators and interactions, as well as pathway dynamics, with respect to both gene expression and cell-cell signaling. Here, focusing primarily on vertebrates, we review the current literature on Notch signaling in the nervous system, and highlight numerous recent studies that have generated interesting and unexpected advances.
  • Mechanisms and Function of Dendritic Exocytosis
    - Neuron (Cambridge Mass ) 69(5):856-875 (2011)
    Dendritic exocytosis is required for a broad array of neuronal functions including retrograde signaling, neurotransmitter release, synaptic plasticity, and establishment of neuronal morphology. While the details of synaptic vesicle exocytosis from presynaptic terminals have been intensely studied for decades, the mechanisms of dendritic exocytosis are only now emerging. Here we review the molecules and mechanisms of dendritic exocytosis and discuss how exocytosis from dendrites influences neuronal function and circuit plasticity.
  • Cytoplasmic Intron Sequence-Retaining Transcripts Can Be Dendritically Targeted via ID Element Retrotransposons
    - Neuron (Cambridge Mass ) 69(5):877-884 (2011)
    RNA precursors give rise to mRNA after splicing of intronic sequences traditionally thought to occur in the nucleus. Here, we show that intron sequences are retained in a number of dendritically-targeted mRNAs, by using microarray and Illumina sequencing of isolated dendritic mRNA as well as in situ hybridization. Many of the retained introns contain ID elements, a class of SINE retrotransposon. A portion of these SINEs confers dendritic targeting to exogenous and endogenous transcripts showing the necessity of ID-mediated mechanisms for the targeting of different transcripts to dendrites. ID elements are capable of selectively altering the distribution of endogenous proteins, providing a link between intronic SINEs and protein function. As such, the ID element represents a common dendritic targeting element found across multiple RNAs. Retention of intronic sequence is a more general phenomenon than previously thought and plays a functional role in the biology of the n! euron, partly mediated by co-opted repetitive sequences.
  • Synaptic Integration Gradients in Single Cortical Pyramidal Cell Dendrites
    - Neuron (Cambridge Mass ) 69(5):885-892 (2011)
    Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from! temporal coding to rate coding along the dendrite.
  • The Cerebrospinal Fluid Provides a Proliferative Niche for Neural Progenitor Cells
    - Neuron (Cambridge Mass ) 69(5):893-905 (2011)
    Cortical development depends on the active integration of cell-autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have criti! cal relevance to normal development and neuropathological conditions.
  • Phosphorylation State of Olig2 Regulates Proliferation of Neural Progenitors
    - Neuron (Cambridge Mass ) 69(5):906-917 (2011)
    The bHLH transcription factors that regulate early development of the central nervous system can generally be classified as either antineural or proneural. Initial expression of antineural factors prevents cell cycle exit and thereby expands the pool of neural progenitors. Subsequent (and typically transient) expression of proneural factors promotes cell cycle exit, subtype specification, and differentiation. Against this backdrop, the bHLH transcription factor Olig2 in the oligodendrocyte lineage is unorthodox, showing antineural functions in multipotent CNS progenitor cells but also sustained expression and proneural functions in the formation of oligodendrocytes. We show here that the proliferative function of Olig2 is controlled by developmentally regulated phosphorylation of a conserved triple serine motif within the amino-terminal domain. In the phosphorylated state, Olig2 maintains antineural (i.e., promitotic) functions that are reflected in human glioma cells ! and in a genetically defined murine model of primary glioma.
  • Phosphorylation Regulates OLIG2 Cofactor Choice and the Motor Neuron-Oligodendrocyte Fate Switch
    - Neuron (Cambridge Mass ) 69(5):918-929 (2011)
    A fundamental feature of central nervous system development is that neurons are generated before glia. In the embryonic spinal cord, for example, a group of neuroepithelial stem cells (NSCs) generates motor neurons (MNs), before switching abruptly to oligodendrocyte precursors (OLPs). We asked how transcription factor OLIG2 participates in this MN-OLP fate switch. We found that Serine 147 in the helix-loop-helix domain of OLIG2 was phosphorylated during MN production and dephosphorylated at the onset of OLP genesis. Mutating Serine 147 to Alanine (S147A) abolished MN production without preventing OLP production in transgenic mice, chicks, or cultured P19 cells. We conclude that S147 phosphorylation, possibly by protein kinase A, is required for MN but not OLP genesis and propose that dephosphorylation triggers the MN-OLP switch. Wild-type OLIG2 forms stable homodimers, whereas mutant (unphosphorylated) OLIG2S147A prefers to form heterodimers with Neurogenin 2 or other ! bHLH partners, suggesting a molecular basis for the switch.
  • An Isoform-Specific SnoN1-FOXO1 Repressor Complex Controls Neuronal Morphogenesis and Positioning in the Mammalian Brain
    - Neuron (Cambridge Mass ) 69(5):930-944 (2011)
    Control of neuronal positioning is fundamental to normal brain development. However, the cell-intrinsic mechanisms that govern neuronal positioning remain to be elucidated. Here, we report that the spliced protein products of the transcriptional regulator SnoN, SnoN1 and SnoN2, harbor opposing functions in the coordinate regulation of neuronal branching and positioning. Knockdown of SnoN2 stimulates axon branching in primary neurons and impairs migration of granule neurons in the rat cerebellar cortex in vivo. By contrast, SnoN1 knockdown suppresses SnoN2 knockdown-induced neuronal branching and strikingly triggers excessive migration of granule neurons in the cerebellar cortex. We also find that SnoN1 forms a complex with the transcription factor FOXO1 that represses the X-linked lissencephaly gene encoding doublecortin (DCX). Accordingly, repression of DCX mediates the ability of SnoN1 to regulate branching in primary neurons and granule neuron migration in vivo. The! se data define an isoform-specific SnoN1-FOXO1 transcriptional complex that orchestrates neuronal branching and positioning in the brain with important implications for the study of developmental disorders of cognition and epilepsy.
  • A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial Segment
    - Neuron (Cambridge Mass ) 69(5):945-956 (2011)
    The axon initial segment (AIS) is critical for the initiation and propagation of action potentials. Assembly of the AIS requires interactions between scaffolding molecules and voltage-gated sodium channels, but the molecular mechanisms that stabilize the AIS are poorly understood. The neuronal isoform of Neurofascin, Nfasc186, clusters voltage-gated sodium channels at nodes of Ranvier in myelinated nerves: here, we investigate its role in AIS assembly and stabilization. Inactivation of the Nfasc gene in cerebellar Purkinje cells of adult mice causes rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier. This causes AIS disintegration, impairment of motor learning and the abolition of the spontaneous tonic discharge typical of Purkinje cells. Nevertheless, action potentials with a modified waveform can still be evoked and basic motor abilities remain intact. We propose that Nfasc186 optimizes communication between mature neurons by anchoring the key elements! of the adult AIS complex.
  • Requirement for Plk2 in Orchestrated Ras and Rap Signaling, Homeostatic Structural Plasticity, and Memory
    - Neuron (Cambridge Mass ) 69(5):957-973 (2011)
    Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the s! ynchronized tuning of Ras and Rap and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
  • Follistatin-like 1 Suppresses Sensory Afferent Transmission by Activating Na+,K+-ATPase
    - Neuron (Cambridge Mass ) 69(5):974-987 (2011)
    Excitatory synaptic transmission is modulated by inhibitory neurotransmitters and neuromodulators. We found that the synaptic transmission of somatic sensory afferents can be rapidly regulated by a presynaptically secreted protein, follistatin-like 1 (FSTL1), which serves as a direct activator of Na+,K+-ATPase (NKA). The FSTL1 protein is highly expressed in small-diameter neurons of the dorsal root ganglion (DRG). It is transported to axon terminals via small translucent vesicles and secreted in both spontaneous and depolarization-induced manners. Biochemical assays showed that FSTL1 binds to the α1 subunit of NKA and elevates NKA activity. Extracellular FSTL1 induced membrane hyperpolarization in cultured cells and inhibited afferent synaptic transmission in spinal cord slices by activating NKA. Genetic deletion of FSTL1 in small DRG neurons of mice resulted in enhanced afferent synaptic transmission and sensory hypersensitivity, which could be reduced by intrathecal! ly applied FSTL1 protein. Thus, FSTL1-dependent activation of NKA regulates the threshold of somatic sensation.
  • TNFα Controls Glutamatergic Gliotransmission in the Hippocampal Dentate Gyrus
    - Neuron (Cambridge Mass ) 69(5):988-1001 (2011)
    Glutamatergic gliotransmission provides a stimulatory input to excitatory synapses in the hippocampal dentate gyrus. Here, we show that tumor necrosis factor-alpha (TNFα) critically controls this process. With constitutive TNFα present, activation of astrocyte P2Y1 receptors induces localized [Ca2+]i elevations followed by glutamate release and presynaptic NMDA receptor-dependent synaptic potentiation. In preparations lacking TNFα, astrocytes respond with identical [Ca2+]i elevations but fail to induce neuromodulation. We find that TNFα specifically controls the glutamate release step of gliotransmission. In cultured astrocytes lacking TNFα glutamate exocytosis is dramatically slowed down due to altered vesicle docking. Addition of low picomolar TNFα promptly reconstitutes both normal exocytosis in culture and gliotransmission in situ. Alternatively, gliotransmission can be re-established without adding TNFα, by limiting glutamate uptake, which compensates slowe! r release. These findings demonstrate that gliotransmission and its synaptic effects are controlled not only by astrocyte [Ca2+]i elevations but also by permissive/homeostatic factors like TNFα. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (20291 K)
  • Uncovering Camouflage: Amygdala Activation Predicts Long-Term Memory of Induced Perceptual Insight
    - Neuron (Cambridge Mass ) 69(5):1002-1014 (2011)
    What brain mechanisms underlie learning of new knowledge from single events? We studied encoding in long-term memory of a unique type of one-shot experience, induced perceptual insight. While undergoing an fMRI brain scan, participants viewed degraded images of real-world pictures where the underlying objects were hard to recognize ("camouflage"), followed by brief exposures to the original images ("solution"), which led to induced insight ("Aha!"). A week later, the participants' memory was tested; a solution image was classified as "remembered" if detailed perceptual knowledge was elicited from the camouflage image alone. During encoding, subsequently remembered images were associated with higher activity in midlevel visual cortex and medial frontal cortex, but most pronouncedly, in the amygdala, whose activity could be used to predict which solutions will remain in long-term memory. Our findings extend the known roles of amygdala in memory to inclu! de promotion of long-term memory of the sudden reorganization of internal representations.
  • Stimulus-Driven Orienting of Visuo-Spatial Attention in Complex Dynamic Environments
    - Neuron (Cambridge Mass ) 69(5):1015-1028 (2011)
    In everyday life attention operates within complex and dynamic environments, while laboratory paradigms typically employ simple and stereotyped stimuli. This fMRI study investigated stimulus-driven spatial attention using a virtual-environment video. We explored the influence of bottom-up signals by computing saliency maps of the environment and by introducing attention-grabbing events in the video. We parameterized the efficacy of these signals for the orienting of spatial attention by measuring eye movements and used these parameters to analyze the imaging data. The efficacy of bottom-up signals modulated ongoing activity in dorsal fronto-parietal regions and transient activation of the ventral attention system. Our results demonstrate that the combination of computational, behavioral, and imaging techniques enables studying cognitive functions in ecologically valid contexts. We highlight the central role of the efficacy of stimulus-driven signals in both dorsal and ! ventral attention systems, with a dissociation of the efficacy of background salience versus distinctive events in the two systems.
  • Entering Adolescence: Resistance to Peer Influence, Risky Behavior, and Neural Changes in Emotion Reactivity
    - Neuron (Cambridge Mass ) 69(5):1029-1036 (2011)
    Adolescence is often described as a period of heightened reactivity to emotions paired with reduced regulatory capacities, a combination suggested to contribute to risk-taking and susceptibility to peer influence during puberty. However, no longitudinal research has definitively linked these behavioral changes to underlying neural development. Here, 38 neurotypical participants underwent two fMRI sessions across the transition from late childhood (10 years) to early adolescence (13 years). Responses to affective facial displays exhibited a combination of general and emotion-specific changes in ventral striatum (VS), ventromedial PFC, amygdala, and temporal pole. Furthermore, VS activity increases correlated with decreases in susceptibility to peer influence and risky behavior. VS and amygdala responses were also significantly more negatively coupled in early adolescence than in late childhood while processing sad and happy versus neutral faces. Together, these results ! suggest that VS responses to viewing emotions may play a regulatory role that is critical to adolescent interpersonal functioning.
  • Gene Expression Profiling of Facilitated L-LTP in VP16-CREB Mice Reveals that BDNF Is Critical for the Maintenance of LTP and Its Synaptic Capture
    - Neuron (Cambridge Mass ) 69(5):1037 (2011)
  • Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors Is Mediated by Inhibition of SK Channels
    - Neuron (Cambridge Mass ) 69(5):1037 (2011)
  • Huntington's Disease: Can Mice Lead the Way to Treatment?
    - Neuron (Cambridge Mass ) 69(5):1038 (2011)

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