Hot off the presses! Jul 16 Neuron

The Jul 16 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:

• Baby Got Brain: Fgf10 Sets Rostral Cortical Size
  - Neuron 63(1):1-3 (2009)
  Brain growth occurs throughout embryogenesis and early postnatal life, but its foundation is laid in the primitive neuroepithelium. In this issue of Neuron, Sahara and O'Leary identify Fgf10 as a key regulator of the neuroepithelial to radial glial transition and subsequently of size of the rostral forebrain.
• According to GOSPEL: Filling in the GAP(DH) of NO-Mediated Neurotoxicity
  - Neuron 63(1):3-6 (2009)
  In addition to its role in glycolysis, GAPDH has been implicated as a mediator of neurotoxicity triggered by nitrosative stress. In this issue of Neuron, Sen et al. identify a novel, negative regulator of this GAPDH neurotoxic pathway termed GOSPEL, which, like GAPDH itself, is regulated by S-nitrosylation.
• It's Lonely at the Top: Winning Climbing Fibers Ascend Dendrites Solo
  - Neuron 63(1):6-8 (2009)
  In mammals, climbing fiber axons compete for sole innervation at each Purkinje cell. At the same time, synapses disappear from Purkinje somata and appear in great numbers on the dendrites. In this issue of Neuron, Hashimoto et al. show that, by the time climbing fibers ascend the dendrites, the winner and losers are already decided.
• Deal Breaker: Semaphorin and Specificity in the Spinal Stretch Reflex Circuit
  - Neuron 63(1):8-11 (2009)
  Stretch reflex circuits are a prime example of wiring specificity in the vertebrate spinal cord. Homonymous sensory afferents and motoneurons typically form monosynaptic connections, while neurons innervating antagonistic or unrelated muscles do not. Pecho-Vrieseling et al. now show that the semaphorin Sema3E and its receptor Plexin-D1 prevent monosynaptic connectivity in the cutaneous maximus muscle stretch reflex circuit.
• Shotgun Proteomics in Neuroscience
  - Neuron 63(1):12-26 (2009)
  Mass spectrometry-based proteomics is increasingly used to address basic and clinical questions in biomedical research through studies of differential protein expression, protein-protein interactions, and posttranslational modifications. The complex structural and functional organization of the human brain warrants the application of high-throughput, systematic approaches to understand the functional alterations under normal physiological conditions and the perturbations of neurological diseases. This primer focuses on shotgun-proteomics-based tandem mass spectrometry for the identification of proteins in a complex mixture. It describes the basic concepts of protein differential expression analysis and posttranslational modification analysis and discusses several strategies to improve the coverage of the proteome.
• Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors
  - Neuron 63(1):27-39 (2009)
  Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased lo! comotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
• In Vivo Cocaine Experience Generates Silent Synapses
  - Neuron 63(1):40-47 (2009)
  Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated postdevelopmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B-containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.
• Fgf10 Regulates Transition Period of Cortical Stem Cell Differentiation to Radial Glia Controlling Generation of Neurons and Basal Progenitors
  - Neuron 63(1):48-62 (2009)
  Radial glia (RG), the progenitors of cortical neurons and basal progenitors (BPs), differentiate from neuroepithelial cells (NCs) with stem cell properties. We show that the morphogen Fgf10 is transiently expressed by NCs coincident with the transition period of NC differentiation into RG. Targeted deletion of Fgf10 delays RG differentiation, whereas overexpression has opposing effects. Delayed RG differentiation in Fgf10 mutants occurs selectively in rostral cortex, paralleled by an extended period of symmetric NC divisions increasing progenitor number, coupled with delayed and initially diminished production of neurons and BPs. RG eventually differentiate in excess number and overproduce neurons and BPs rostrally resulting in tangential expansion of frontal areas and increased laminar thickness. Thus, transient Fgf10 expression regulates timely differentiation of RG, and through this function, determines both length of the early progenitor expansion phase and onset o! f neurogenesis and ultimately the number of progenitors and neurons fated to specific cortical areas.
• Myosin II Motors and F-Actin Dynamics Drive the Coordinated Movement of the Centrosome and Soma during CNS Glial-Guided Neuronal Migration
  - Neuron 63(1):63-80 (2009)
  Lamination of cortical regions of the vertebrate brain depends on glial-guided neuronal migration. The conserved polarity protein Par6α localizes to the centrosome and coordinates forward movement of the centrosome and soma in migrating neurons. The cytoskeletal components that produce this unique form of cell polarity and their relationship to polarity signaling cascades are unknown. We show that F-actin and Myosin II motors are enriched in the neuronal leading process and that Myosin II activity is necessary for leading process actin dynamics. Inhibition of Myosin II decreased the speed of centrosome and somal movement, whereas Myosin II activation increased coordinated movement. Ectopic expression or silencing of Par6α inhibited Myosin II motors by decreasing Myosin light-chain phosphorylation. These findings suggest leading-process Myosin II may function to "pull" the centrosome and soma forward during glial-guided migration by a mechanism involving the conse! rved polarity protein Par6α.
• GOSPEL: A Neuroprotective Protein that Binds to GAPDH upon S-Nitrosylation
  - Neuron 63(1):81-91 (2009)
  We recently reported a cell death cascade whereby cellular stressors activate nitric oxide formation leading to S-nitrosylation of GAPDH that binds to Siah and translocates to the nucleus. The nuclear GAPDH/Siah complex augments p300/CBP-associated acetylation of nuclear proteins, including p53, which mediate cell death. We report a 52 kDa cytosolic protein, GOSPEL, which physiologically binds GAPDH, in competition with Siah, retaining GAPDH in the cytosol and preventing its nuclear translocation. GOSPEL is neuroprotective, as its overexpression prevents NMDA-glutamate excitotoxicity while its depletion enhances death in primary neuron cultures. S-nitrosylation of GOSPEL at cysteine 47 enhances GAPDH-GOSPEL binding and the neuroprotective actions of GOSPEL. In intact mice, virally delivered GOSPEL selectively diminishes NMDA neurotoxicity. Thus, GOSPEL may physiologically regulate the viability of neurons and other cells.
• Endocytic Trafficking and Recycling Maintain a Pool of Mobile Surface AMPA Receptors Required for Synaptic Potentiation
  - Neuron 63(1):92-105 (2009)
  At excitatory glutamatergic synapses, postsynaptic endocytic zones (EZs), which are adjacent to the postsynaptic density (PSD), mediate clathrin-dependent endocytosis of surface AMPA receptors (AMPAR) as a first step to receptor recycling or degradation. However, it remains unknown whether receptor recycling influences AMPAR lateral diffusion and whether EZs are important for the expression of synaptic potentiation. Here, we demonstrate that the presence of both EZs and AMPAR recycling maintain a large pool of mobile AMPARs at synapses. In addition, we find that synaptic potentiation is accompanied by an accumulation and immobilization of AMPARs at synapses resulting from both their exocytosis and stabilization at the PSD. Displacement of EZs from the postsynaptic region impairs the expression of synaptic potentiation by blocking AMPAR recycling. Thus, receptor recycling is crucial for maintaining a mobile population of surface AMPARs that can be delivered to synapses ! for increases in synaptic strength.
• Translocation of a "Winner" Climbing Fiber to the Purkinje Cell Dendrite and Subsequent Elimination of "Losers" from the Soma in Developing Cerebellum
  - Neuron 63(1):106-118 (2009)
  Functional neural circuits are formed by eliminating early-formed redundant synapses and strengthening necessary connections during development. In newborn mouse cerebellum, each Purkinje cell (PC) is innervated by multiple climbing fibers (CFs) with similar strengths. Subsequently, a single CF is selectively strengthened by postnatal day 7 (P7). We find that this competition among multiple CFs occurs on the soma before CFs form synapses along dendrites. Notably, in most PCs, the single CF that has been functionally strengthened (the "winner" CF) undergoes translocation to dendrites while keeping its synapses on the soma. Synapses of the weaker CFs (the "loser" CFs) remain around the soma and form "pericellular nests" with synapses of the winner CFs. Then most perisomatic synapses are eliminated nonselectively by P15. Thus, our results suggest that the selective translocation of the winner CF to dendrites in each PC determines the single CF that survives su! bsequent synapse elimination and persistently innervates the PC.
• Midbrain Dopamine Neurons Signal Preference for Advance Information about Upcoming Rewards
  - Neuron 63(1):119-126 (2009)
  The desire to know what the future holds is a powerful motivator in everyday life, but it is unknown how this desire is created by neurons in the brain. Here we show that when macaque monkeys are offered a water reward of variable magnitude, they seek advance information about its size. Furthermore, the same midbrain dopamine neurons that signal the expected amount of water also signal the expectation of information, in a manner that is correlated with the strength of the animal's preference. Our data show that single dopamine neurons process both primitive and cognitive rewards, and suggest that current theories of reward-seeking must be revised to include information-seeking.
• Training Improves Multitasking Performance by Increasing the Speed of Information Processing in Human Prefrontal Cortex
  - Neuron 63(1):127-138 (2009)
  Our ability to multitask is severely limited: task performance deteriorates when we attempt to undertake two or more tasks simultaneously. Remarkably, extensive training can greatly reduce such multitasking costs. While it is not known how training alters the brain to solve the multitasking problem, it likely involves the prefrontal cortex given this brain region's purported role in limiting multitasking performance. Here, we show that the reduction of multitasking interference with training is not achieved by diverting the flow of information processing away from the prefrontal cortex or by segregating prefrontal cells into independent task-specific neuronal ensembles, but rather by increasing the speed of information processing in this brain region, thereby allowing multiple tasks to be processed in rapid succession. These results not only reveal how training leads to efficient multitasking, they also provide a mechanistic account of multitasking limitations, namely ! the poor speed of information processing in human prefrontal cortex.
• Reading the Book of Memory: Sparse Sampling versus Dense Mapping of Connectomes
  - Neuron 63(1):139 (2009)