Hot off the presses! Nov 18 Neuron

The Nov 18 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:

• Sorting Out Frontotemporal Dementia?
  - Neuron (Cambridge Mass ) 68(4):601-603 (2010)
  Mutations within the granulin (GRN) gene that encodes progranulin (PGRN) cause the neurodegenerative disease frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U). The receptor for PGRN in the CNS has not been previously identified. In this issue of Neuron, Hu and colleagues identify Sortilin (SORT1) as a key neuronal receptor for PGRN that facilitates its endocytosis and regulates PGRN levels in vitro and in vivo.
• The Cytomatrix Protein Bassoon Contributes to Fast Transmission at Conventional and Ribbon Synapses
  - Neuron (Cambridge Mass ) 68(4):604-606 (2010)
  The presynaptic active zone contains a complex web of proteins involved in synaptic transmission. In this issue of Neuron, two articles show evidence that one of these proteins, Bassoon, coordinates multiple functions in a conventional and ribbon-type synapse.
• A Recipe for Bidirectional Motor Learning: Using Inhibition to Cook Plasticity in the Vestibular Nuclei
  - Neuron (Cambridge Mass ) 68(4):607-609 (2010)
  In this issue of Neuron, McElvain et al. demonstrate for the first time plasticity at the synapse between vestibular nerve afferents and their postsynaptic targets in the medial vestibular nuclei. This new type of plasticity, which is gated by inhibition, is well suited to drive motor learning during adaptation of the vestibulo-ocular reflex.
• Molecular Motors in Neurons: Transport Mechanisms and Roles in Brain Function, Development, and Disease
  - Neuron (Cambridge Mass ) 68(4):610-638 (2010)
  The kinesin, dynein, and myosin superfamily molecular motors have fundamental roles in neuronal function, plasticity, morphogenesis, and survival by transporting cargos such as synaptic vesicle precursors, neurotransmitter and neurotrophic factor receptors, and mRNAs within axons, dendrites, and synapses. Recent studies have begun to clarify the mechanisms of cargo selection and directional transport in subcellular compartments. Furthermore, molecular genetics has revealed unexpected roles for molecular motors in brain wiring, neuronal survival, neuronal plasticity, higher brain function, and control of central nervous system and peripheral nervous system development. Finally, it is also evident that molecular motors are critically involved in neuronal disease pathogenesis. Thus, molecular motor research is becoming an exciting frontier of neuroscience.
• Single-Synapse Analysis of a Diverse Synapse Population: Proteomic Imaging Methods and Markers
  - Neuron (Cambridge Mass ) 68(4):639-653 (2010)
  A lack of methods for measuring the protein compositions of individual synapses in situ has so far hindered the exploration and exploitation of synapse molecular diversity. Here, we describe the use of array tomography, a new high-resolution proteomic imaging method, to determine the composition of glutamate and GABA synapses in somatosensory cortex of Line-H-YFP Thy-1 transgenic mice. We find that virtually all synapses are recognized by antibodies to the presynaptic phosphoprotein synapsin I, while antibodies to 16 other synaptic proteins discriminate among 4 subtypes of glutamatergic synapses and GABAergic synapses. Cell-specific YFP expression in the YFP-H mouse line allows synapses to be assigned to specific presynaptic and postsynaptic partners and reveals that a subpopulation of spines on layer 5 pyramidal cells receives both VGluT1-subtype glutamatergic and GABAergic synaptic inputs. These results establish a means for the high-throughput acquisition of proteom! ic data from individual cortical synapses in situ.
• Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin
  - Neuron (Cambridge Mass ) 68(4):654-667 (2010)
  The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1−/− neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/− mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central! role in FTLD-TDP pathophysiology. 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 (19939 K)
• NG2+ CNS Glial Progenitors Remain Committed to the Oligodendrocyte Lineage in Postnatal Life and following Neurodegeneration
  - Neuron (Cambridge Mass ) 68(4):668-681 (2010)
  The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential and that cell loss and gliosis are not sufficient to alter the l! ineage potential of these progenitors.
• The Transcription Factor Pax6 Regulates Survival of Dopaminergic Olfactory Bulb Neurons via Crystallin αA
  - Neuron (Cambridge Mass ) 68(4):682-694 (2010)
  Most neurons in the adult mammalian brain survive for the entire life of an individual. However, it is not known which transcriptional pathways regulate this survival in a healthy brain. Here, we identify a pathway regulating neuronal survival in a highly subtype-specific manner. We show that the transcription factor Pax6 expressed in dopaminergic neurons of the olfactory bulb regulates the survival of these neurons by directly controlling the expression of crystallin αA (CryαA), which blocks apoptosis by inhibition of procaspase-3 activation. Re-expression of CryαA fully rescues survival of Pax6-deficient dopaminergic interneurons in vivo and knockdown of CryαA by shRNA in wild-type mice reduces the number of dopaminergic OB interneurons. Strikingly, Pax6 utilizes different DNA-binding domains for its well-known role in fate specification and this role of regulating the survival of specific neuronal subtypes in the mature, healthy brain.
• Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration
  - Neuron (Cambridge Mass ) 68(4):695-709 (2010)
  Coordinated migration of newly born neurons to their prospective target laminae is a prerequisite for neural circuit assembly in the developing brain. The evolutionarily conserved LIS1/NDEL1 complex is essential for neuronal migration in the mammalian cerebral cortex. The cytoplasmic nature of LIS1 and NDEL1 proteins suggest that they regulate neuronal migration cell autonomously. Here, we extend mosaic analysis with double markers (MADM) to mouse chromosome 11 where Lis1, Ndel1, and 14-3-3 (encoding a LIS1/NDEL1 signaling partner) are located. Analyses of sparse and uniquely labeled mutant cells in mosaic animals reveal distinct cell-autonomous functions for these three genes. Lis1 regulates neuronal migration efficiency in a dose-dependent manner, while Ndel1 is essential for a specific, previously uncharacterized, late step of neuronal migration: entry into the target lamina. Comparisons with previous genetic perturbations of Lis1 and Ndel1 also suggest a surprising! degree of cell-nonautonomous function for these proteins in regulating neuronal migration.
• Bassoon Speeds Vesicle Reloading at a Central Excitatory Synapse
  - Neuron (Cambridge Mass ) 68(4):710-723 (2010)
  Sustained rate-coded signals encode many types of sensory modalities. Some sensory synapses possess specialized ribbon structures, which tether vesicles, to enable high-frequency signaling. However, central synapses lack these structures, yet some can maintain signaling over a wide bandwidth. To analyze the underlying molecular mechanisms, we investigated the function of the active zone core component Bassoon in cerebellar mossy fiber to granule cell synapses. We show that short-term synaptic depression is enhanced in Bassoon knockout mice during sustained high-frequency trains but basal synaptic transmission is unaffected. Fluctuation and quantal analysis as well as quantification with constrained short-term plasticity models revealed that the vesicle reloading rate was halved in the absence of Bassoon. Thus, our data show that the cytomatrix protein Bassoon speeds the reloading of vesicles to release sites at a central excitatory synapse.
• Bassoon and the Synaptic Ribbon Organize Ca2+ Channels and Vesicles to Add Release Sites and Promote Refilling
  - Neuron (Cambridge Mass ) 68(4):724-738 (2010)
  At the presynaptic active zone, Ca2+ influx triggers fusion of synaptic vesicles. It is not well understood how Ca2+ channel clustering and synaptic vesicle docking are organized. Here, we studied structure and function of hair cell ribbon synapses following genetic disruption of the presynaptic scaffold protein Bassoon. Mutant synapses—mostly lacking the ribbon—showed a reduction in membrane-proximal vesicles, with ribbonless synapses affected more than ribbon-occupied synapses. Ca2+ channels were also fewer at mutant synapses and appeared in abnormally shaped clusters. Ribbon absence reduced Ca2+ channel numbers at mutant and wild-type synapses. Fast and sustained exocytosis was reduced, notwithstanding normal coupling of the remaining Ca2+ channels to exocytosis. In vitro recordings revealed a slight impairment of vesicle replenishment. Mechanistic modeling of the in vivo data independently supported morphological and functional in vitro findings. We conclude th! at Bassoon and the ribbon (1) create a large number of release sites by organizing Ca2+ channels and vesicles, and (2) promote vesicle replenishment.
• Sensing Muscle Ischemia: Coincident Detection of Acid and ATP via Interplay of Two Ion Channels
  - Neuron (Cambridge Mass ) 68(4):739-749 (2010)
  Ischemic pain—examples include the chest pain of a heart attack and the leg pain of a 30 s sprint—occurs when muscle gets too little oxygen for its metabolic need. Lactic acid cannot act alone to trigger ischemic pain because the pH change is so small. Here, we show that another compound released from ischemic muscle, adenosine tri-phosphate (ATP), works together with acid by increasing the pH sensitivity of acid-sensing ion channel number 3 (ASIC3), the molecule used by sensory neurons to detect lactic acidosis. Our data argue that ATP acts by binding to P2X receptors that form a molecular complex with ASICs; the receptor on sensory neurons appears to be P2X5, an electrically quiet ion channel. Coincident detection of acid and ATP should confer sensory selectivity for ischemia over other conditions of acidosis.
• Visual Deprivation Suppresses L5 Pyramidal Neuron Excitability by Preventing the Induction of Intrinsic Plasticity
  - Neuron (Cambridge Mass ) 68(4):750-762 (2010)
  In visual cortex monocular deprivation (MD) during a critical period (CP) reduces the ability of the deprived eye to activate cortex, but the underlying cellular plasticity mechanisms are incompletely understood. Here we show that MD reduces the intrinsic excitability of layer 5 (L5) pyramidal neurons and enhances long-term potentiation of intrinsic excitability (LTP-IE). Further, MD and LTP-IE induce reciprocal changes in Kv2.1 current, and LTP-IE reverses the effects of MD on intrinsic excitability. Taken together these data suggest that MD reduces intrinsic excitability by preventing sensory-drive induced LTP-IE. The effects of MD on excitability were correlated with the classical visual system CP, and (like the functional effects of MD) could be rapidly reversed when vision was restored. These data establish LTP-IE as a candidate mechanism mediating loss of visual responsiveness within L5, and suggest that intrinsic plasticity plays an important role in experience-! dependent refinement of visual cortical circuits.
• Bidirectional Plasticity Gated by Hyperpolarization Controls the Gain of Postsynaptic Firing Responses at Central Vestibular Nerve Synapses
  - Neuron (Cambridge Mass ) 68(4):763-775 (2010)
  Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional,! linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.
• Human Posterior Parietal Cortex Flexibly Determines Reference Frames for Reaching Based on Sensory Context
  - Neuron (Cambridge Mass ) 68(4):776-788 (2010)
  Current models of sensorimotor transformations emphasize the dominant role of gaze-centered representations for reach planning in the posterior parietal cortex (PPC). Here we exploit fMRI repetition suppression to test whether the sensory modality of a target determines the reference frame used to define the motor goal in the PPC and premotor cortex. We show that when targets are defined visually, the anterior precuneus selectively encodes the motor goal in gaze-centered coordinates, whereas the parieto-occipital junction, Brodman Area 5 (BA 5), and PMd use a mixed gaze- and body-centered representation. In contrast, when targets are defined by unseen proprioceptive cues, activity in these areas switches to represent the motor goal predominantly in body-centered coordinates. These results support computational models arguing for flexibility in reference frames for action according to sensory context. Critically, they provide neuroanatomical evidence that flexibility is! achieved by exploiting a multiplicity of reference frames that can be expressed within individual areas.
• Coding of Reward Risk by Orbitofrontal Neurons Is Mostly Distinct from Coding of Reward Value
  - Neuron (Cambridge Mass ) 68(4):789-800 (2010)
  Risky decision-making is altered in humans and animals with damage to the orbitofrontal cortex. However, the cellular function of the intact orbitofrontal cortex in processing information relevant for risky decisions is unknown. We recorded responses of single orbitofrontal neurons while monkeys viewed visual cues representing the key decision parameters, reward risk and value. Risk was defined as the mathematical variance of binary symmetric probability distributions of reward magnitudes; value was defined as nonrisky reward magnitude. Monkeys displayed graded behavioral preferences for risky outcomes, as they did for value. A population of orbitofrontal neurons showed a distinctive risk signal: their cues and reward responses covaried monotonically with the variance of the different reward distributions without monotonically coding reward value. Furthermore, a small but statistically significant fraction of risk responses also coded reward value. These risk signals m! ay provide physiological correlates for the role of the orbitofrontal cortex in risk processing.
• Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
  - Neuron (Cambridge Mass ) 68(4):801 (2010)
  
• Electrical Coupling between Olfactory Glomeruli
  - Neuron (Cambridge Mass ) 68(4):801 (2010)