Hot off the presses! Jan 27 Neuron

The Jan 27 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:

• Controlled Demolition: Smurf1 Regulates Neuronal Polarity by Substrate Switching
  - Neuron (Cambridge Mass ) 69(2):183-185 (2011)
  During axon specification, growth promoting proteins localize selectively to the growing axon. In this issue of Neuron, Cheng et al. report how selective protein degradation, controlled by a substrate switch of the ubiquitin ligase Smurf1, specifies Par6 and RhoA localization and thereby regulates neuronal polarity.
• The Multiple Faces of RIM
  - Neuron (Cambridge Mass ) 69(2):185-187 (2011)
  Rab3 interacting molecules (RIMs) are highly enriched in the active zones of presynaptic terminals. It is generally thought that they operate as effectors of the small G protein Rab3. Three recent papers, by Han et al. (this issue of Neuron), Deng et al. (this issue of Neuron), and Kaeser et al. (a recent issue of Cell), shed new light on the functional role of RIM in presynaptic terminals. First, RIM tethers Ca2+ channels to active zones. Second, RIM contributes to priming of synaptic vesicles by interacting with another presynaptic protein, Munc13.
• Stressed and Depressed? Check Your GDNF for Epigenetic Repression
  - Neuron (Cambridge Mass ) 69(2):188-190 (2011)
  Some adults fail to adapt to chronic stress, developing symptoms of depression and anxiety. In this issue of Neuron, Uchida and colleagues link maladaptive stress responses to GDNF through a comprehensive investigation of the neurotrophic factor's regulation. Further, this study is an excellent example for investigators interested in neuroepigenetics research.
• Dynamic Formation of Functional Networks by Synchronization
  - Neuron (Cambridge Mass ) 69(2):191-193 (2011)
  The cerebral cortex consists of numerous, densely interconnected, functionally specialized areas that need to cooperate in ever-changing constellations depending on the actual cognitive or executive task. One way to achieve this dynamic coordination could be phase-locking of synchronized oscillatory activity. In this issue of Neuron, Hipp et al. provide supportive evidence by analyzing EEG signals associated with an ambiguous audiovisual discrimination task.
• Out of Thin Air: Sensory Detection of Oxygen and Carbon Dioxide
  - Neuron (Cambridge Mass ) 69(2):194-202 (2011)
  Oxygen (O2) and carbon dioxide (CO2) levels vary in different environments and locally fluctuate during respiration and photosynthesis. Recent studies in diverse animals have identified sensory neurons that detect these external variations and direct a variety of behaviors. Detection allows animals to stay within a preferred environment as well as identify potential food or dangers. The complexity of sensation is reflected in the fact that neurons compartmentalize detection into increases, decreases, and short-range and long-range cues. Animals also adjust their responses to these prevalent signals in the context of other cues, allowing for flexible behaviors. In general, the molecular mechanisms for detection suggest that sensory neurons adopted ancient strategies for cellular detection and coupled them to brain activity and behavior. This review highlights the multiple strategies that animals use to extract information about their environment from variations in O2 an! d CO2.
• Anti-Aβ Therapeutics in Alzheimer's Disease: The Need for a Paradigm Shift
  - Neuron (Cambridge Mass ) 69(2):203-213 (2011)
  Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.
• Dual Roles of Notch in Regulation of Apically Restricted Mitosis and Apicobasal Polarity of Neuroepithelial Cells
  - Neuron (Cambridge Mass ) 69(2):215-230 (2011)
  How the mitosis of neuroepithelial stem cells is restricted to the apical ventricular area remains unclear. In zebrafish, the mosaic eyesrw306 (moe/epb41l5rw306) mutation disrupts the interaction between the putative adaptor protein Moe and the apicobasal polarity regulator Crumbs (Crb), and impairs the maintenance of neuroepithelial apicobasal polarity. While Crb interacts directly with Notch and inhibits its activity, Moe reverses this inhibition. In the moerw306 hindbrain, Notch activity is significantly reduced, and the number of cells that proliferate basally away from the apical area is increased. Surprisingly, activation of Notch in the moerw306 mutant rescues not only the basally localized proliferation but also the aberrant neuroepithelial apicobasal polarity. We present evidence that the CrbMoe complex and Notch play key roles in a positive feedback loop to maintain the apicobasal polarity and the apical-high basal-low gradient of Notch activity in neuroepith! elial cells, both of which are essential for their apically restricted mitosis.
• Phosphorylation of E3 Ligase Smurf1 Switches Its Substrate Preference in Support of Axon Development
  - Neuron (Cambridge Mass ) 69(2):231-243 (2011)
  Ubiquitin E3 ligases serve for ubiquitination of specific substrates, and its ligase efficacy is regulated by interacting proteins or substrate modifications. Whether and how the ligases themselves are modified by cellular signaling is unclear. Here we report that protein kinase A (PKA)-dependent phosphorylation of Smad Ubiquitin Regulatory Factor 1 (Smurf1) can switch its substrate preference between two proteins of opposing actions on axon development. Extracellular factors that promote axon formation elevated Smurf1 phosphorylation at a PKA site Thr306, and preventing this phosphorylation reduced axon formation in cultured hippocampal neurons and impaired polarization of cortical neurons in vivo. Thr306-phosphorylation changed the relative affinities of Smurf1 for its substrates, leading to reduced degradation of polarity protein Par6 and increased degradation of growth-inhibiting RhoA. Thus, PKA-dependent phosphorylation of the E3 ligase could switch its substrate ! preference, contributing to selective protein degradation required for localized cellular function.
• Nodes of Ranvier Act as Barriers to Restrict Invasion of Flanking Paranodal Domains in Myelinated Axons
  - Neuron (Cambridge Mass ) 69(2):244-257 (2011)
  Accumulation of voltage-gated sodium (Nav) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization, and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (NfascNF186) in vivo results in nodal disorganization, including loss of Nav channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral nervous system (PNS) and central nervous system (CNS). Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in NfascNF186 mutant axons and occlude node formation. Our results suggest that NfascNF186-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area! , thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons.
• The Molecular and Cellular Basis of Bitter Taste in Drosophila
  - Neuron (Cambridge Mass ) 69(2):258-272 (2011)
  The extent of diversity among bitter-sensing neurons is a fundamental issue in the field of taste. Data are limited and conflicting as to whether bitter neurons are broadly tuned and uniform, resulting in indiscriminate avoidance of bitter stimuli, or diverse, allowing a more discerning evaluation of food sources. We provide a systematic analysis of how bitter taste is encoded by the major taste organ of the Drosophila head, the labellum. Each of 16 bitter compounds is tested physiologically against all 31 taste hairs, revealing responses that are diverse in magnitude and dynamics. Four functional classes of bitter neurons are defined. Four corresponding classes are defined through expression analysis of all 68 gustatory taste receptors. A receptor-to-neuron-to-tastant map is constructed. Misexpression of one receptor confers bitter responses as predicted by the map. These results reveal a degree of complexity that greatly expands the capacity of the system to encode b! itter taste.
• In Vivo Time-Lapse Imaging and Serial Section Electron Microscopy Reveal Developmental Synaptic Rearrangements
  - Neuron (Cambridge Mass ) 69(2):273-286 (2011)
  Dendrites, axons, and synapses are dynamic during circuit development; however, changes in microcircuit connections as branches stabilize have not been directly demonstrated. By combining in vivo time-lapse imaging of Xenopus tectal neurons with electron microscope reconstructions of imaged neurons, we report the distribution and ultrastructure of synapses on individual vertebrate neurons and relate these synaptic properties to dynamics in dendritic and axonal arbor structure over hours or days of imaging. Dynamic dendrites have a high density of immature synapses, whereas stable dendrites have sparser, mature synapses. Axons initiate contacts from multisynapse boutons on stable branches. Connections are refined by decreasing convergence from multiple inputs to postsynaptic dendrites and by decreasing divergence from multisynapse boutons to postsynaptic sites. Visual deprivation or NMDAR antagonists decreased synapse maturation and elimination, suggesting that coactive! input activity promotes microcircuit development by concurrently regulating synapse elimination and maturation of remaining contacts.
• Postsynaptic TrkC and Presynaptic PTPσ Function as a Bidirectional Excitatory Synaptic Organizing Complex
  - Neuron (Cambridge Mass ) 69(2):287-303 (2011)
  Neurotrophin receptor tyrosine kinases (Trks) have well-defined trophic roles in nervous system development through kinase activation by neurotrophins. Yet Trks have typical cell-adhesion domains and express noncatalytic isoforms, suggesting additional functions. Here we discovered noncatalytic TrkC in an unbiased hippocampal neuron-fibroblast coculture screen for proteins that trigger differentiation of neurotransmitter release sites in axons. All TrkC isoforms, but not TrkA or TrkB, function directly in excitatory glutamatergic synaptic adhesion by neurotrophin-independent high-affinity trans binding to axonal protein tyrosine phosphatase receptor PTPσ. PTPσ triggers and TrkC mediates clustering of postsynaptic molecules in dendrites, indicating bidirectional synaptic organizing functions. Effects of a TrkC-neutralizing antibody that blocks TrkC-PTPσ interaction and TrkC knockdown in culture and in vivo reveal essential roles of TrkC-PTPσ in glutamatergic synapse! formation. Thus, postsynaptic TrkC trans interaction with presynaptic PTPσ generates bidirectional adhesion and recruitment essential for excitatory synapse development and positions these signaling molecules at the center of synaptic pathways.
• RIM Determines Ca2+ Channel Density and Vesicle Docking at the Presynaptic Active Zone
  - Neuron (Cambridge Mass ) 69(2):304-316 (2011)
  At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca2+ channels close to docked vesicles. The mechanisms that enrich Ca2+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knockout approach at a presynaptically accessible central nervous system synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca2+ channel density, revealing a role of RIM proteins in Ca2+ channel targeting. Removal of RIMs also reduced the readily releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca2+ channel-vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release, enabling a high presynaptic Ca2+ channel density and vesicle dock! ing at the active zone.
• RIM Proteins Activate Vesicle Priming by Reversing Autoinhibitory Homodimerization of Munc13
  - Neuron (Cambridge Mass ) 69(2):317-331 (2011)
  At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that—among others—mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn2+ finger domain of RIMs binds to the C2A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it. Here, we show that RIMs mediate vesicle priming not by coupling Munc13 to other active zone proteins as thought but by directly activating Munc13. Specifically, we found that the isolated Zn2+ finger domain of RIMs autonomously promoted vesicle priming by binding to Munc13, thereby relieving Munc13 homodimerization. Strikingly, constitutively monomeric mutants of Munc13 rescued priming in RIM-deficient synapses, whereas wild-type Munc13 did not. Both mutant and wild-type Munc13, however, rescued priming in Munc13-deficient synapses. Thus, homo! dimerization of Munc13 inhibits its priming function, and RIMs activate priming by disrupting Munc13 homodimerization.
• The Molecular and Cellular Identity of Peripheral Osmoreceptors
  - Neuron (Cambridge Mass ) 69(2):332-344 (2011)
  In mammals, the osmolality of the extracellular fluid (ECF) is highly stable despite radical changes in salt/water intake and excretion. Afferent systems are required to detect hypo- or hyperosmotic shifts in the ECF to trigger homeostatic control of osmolality. In humans, a pressor reflex is triggered by simply drinking water which may be mediated by peripheral osmoreceptors. Here, we identified afferent neurons in the thoracic dorsal root ganglia (DRG) of mice that innervate hepatic blood vessels and detect physiological hypo-osmotic shifts in blood osmolality. Hepatic sensory neurons are equipped with an inward current that faithfully transduces graded changes in osmolality within the physiological range (15 mOsm). In mice lacking the osmotically activated ion channel, TRPV4, hepatic sensory neurons no longer exhibit osmosensitive inward currents and activation of peripheral osmoreceptors in vivo is abolished. We have thus identified a new population of sensory neur! ons that transduce ongoing changes in hepatic osmolality.
• Sun Compass Integration of Skylight Cues in Migratory Monarch Butterflies
  - Neuron (Cambridge Mass ) 69(2):345-358 (2011)
  Migrating monarch butterflies (Danaus plexippus) use a time-compensated sun compass to navigate from eastern North America to their overwintering grounds in central Mexico. Here we describe the neuronal layout of those aspects of the butterfly's central complex likely to establish part of the internal sun compass and find them highly homologous to those of the desert locust. Intracellular recordings from neurons in the monarch sun compass network reveal responses tuned to specific E-vector angles of polarized light, as well as azimuth-dependent responses to unpolarized light, independent of spectral composition. The neural responses to these two stimuli in individual neurons are mediated through different regions of the compound eye. Moreover, these dual responses are integrated to create a consistent representation of skylight cues in the sun compass throughout the day. The results advance our understanding of how ambiguous sensory signals are processed by the brain t! o elicit a robust behavioral response. 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 (33600 K)
• Epigenetic Status of Gdnf in the Ventral Striatum Determines Susceptibility and Adaptation to Daily Stressful Events
  - Neuron (Cambridge Mass ) 69(2):359-372 (2011)
  Stressful events during adulthood are potent adverse environmental factors that can predispose individuals to psychiatric disorders, including depression; however, many individuals exposed to stressful events can adapt and function normally. While stress vulnerability may influence depression, the molecular mechanisms underlying the susceptibility and adaptation to chronic stress within the brain are poorly understood. In this study, two genetically distinct mouse strains that exhibit different behavioral responses to chronic stress were used to demonstrate how the differential epigenetic status of the glial cell-derived neurotrophic factor (Gdnf) gene in the ventral striatum modulates susceptibility and adaptation to chronic stress. Our results suggest that the histone modifications and DNA methylation of the Gdnf promoter have crucial roles in the control of behavioral responses to chronic stress. Our data provide insights into these mechanisms, suggesting that epige! netic modifications of Gdnf, along with genetic and environmental factors, contribute to behavioral responses to stress.
• Using the Structure of Inhibitory Networks to Unravel Mechanisms of Spatiotemporal Patterning
  - Neuron (Cambridge Mass ) 69(2):373-386 (2011)
  Neuronal networks exhibit a rich dynamical repertoire, a consequence of both the intrinsic properties of neurons and the structure of the network. It has been hypothesized that inhibitory interneurons corral principal neurons into transiently synchronous ensembles that encode sensory information and subserve behavior. How does the structure of the inhibitory network facilitate such spatiotemporal patterning? We established a relationship between an important structural property of a network, its colorings, and the dynamics it constrains. Using a model of the insect antennal lobe, we show that our description allows the explicit identification of the groups of inhibitory interneurons that switch, during odor stimulation, between activity and quiescence in a coordinated manner determined by features of the network structure. This description optimally matches the perspective of the downstream neurons looking for synchrony in ensembles of presynaptic cells and allows a lo! w-dimensional description of seemingly complex high-dimensional network activity.
• Oscillatory Synchronization in Large-Scale Cortical Networks Predicts Perception
  - Neuron (Cambridge Mass ) 69(2):387-396 (2011)
  Normal brain function requires the dynamic interaction of functionally specialized but widely distributed cortical regions. Long-range synchronization of oscillatory signals has been suggested to mediate these interactions within large-scale cortical networks, but direct evidence is sparse. Here we show that oscillatory synchronization is organized in such large-scale networks. We implemented an analysis approach that allows for imaging synchronized cortical networks and applied this technique to EEG recordings in humans. We identified two networks: beta-band synchronization (20 Hz) in a fronto-parieto-occipital network and gamma-band synchronization (80 Hz) in a centro-temporal network. Strong perceptual correlates support their functional relevance: the strength of synchronization within these networks predicted the subjects' percept of an ambiguous audiovisual stimulus as well as the integration of auditory and visual information. Our results provide evidence that o! scillatory neuronal synchronization mediates neuronal communication within frequency-specific, large-scale cortical networks.
• Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
  - Neuron (Cambridge Mass ) 69(2):397 (2011)