Hot off the presses! Apr 28 Neuron

The Apr 28 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:

• A New, Blue Gene Highlights Glutamate and Hippocampus in Depression
  - Neuron (Cambridge Mass ) 70(2):171-172 (2011)
  Depression is a common and debilitating psychiatric syndrome with a complex risk architecture marked by interacting genetic and environmental factors. In this issue of Neuron, the study by Kohli et al. (2011) reports a novel genome-wide supported risk variant for depression that affects hippocampal gene expression, anatomy, and biochemistry.
• Out-of-Place Bodies, Out-of-Body Selves
  - Neuron (Cambridge Mass ) 70(2):173-175 (2011)
  In this issue of Neuron, Ionta et al. (2011) combine behavioral and fMRI approaches with anatomical lesion data to show that illusory perception of one's own body from an external point of view or at a different physical location is linked to modulation of neural activity in the temporo-parietal-junction, a cortical region fundamental to body-consciousness.
• Cracking the Combinatorial Semaphorin Code
  - Neuron (Cambridge Mass ) 70(2):175-177 (2011)
  In this issue of Neuron, Wu et al. describe a combinatorial code of repulsive Sema-2a and attractive Sema-2b signaling that mediates mechanosensory axonal guidance, fasciculation, and synaptic target selection within the CNS of Drosophila. Their work exemplifies how a detailed, multilevel molecular-genetic analysis (from molecules to behavior) provides fundamental insights into neural circuit development.
• The Expanding Social Network of Ionotropic Glutamate Receptors: TARPs and Other Transmembrane Auxiliary Subunits
  - Neuron (Cambridge Mass ) 70(2):178-199 (2011)
  Ionotropic glutamate receptors (iGluRs) underlie rapid, excitatory synaptic signaling throughout the CNS. After years of intense research, our picture of iGluRs has evolved from them being companionless in the postsynaptic membrane to them being the hub of dynamic supramolecular signaling complexes, interacting with an ever-expanding litany of other proteins that regulate their trafficking, scaffolding, stability, signaling, and turnover. In particular, the discovery that transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary subunits that are critical determinants of their trafficking, gating, and pharmacology has changed the way we think about iGluR function. Recently, a number of novel transmembrane proteins have been uncovered that may also serve as iGluR auxiliary proteins. Here we review pivotal developments in our understanding of the role of TARPs in AMPA receptor trafficking and gating, and provide an overview of how newly discover! ed transmembrane proteins expand our view of iGluR function in the CNS.
• Experimental and Theoretical Approaches to Conscious Processing
  - Neuron (Cambridge Mass ) 70(2):200-227 (2011)
  Recent experimental studies and theoretical models have begun to address the challenge of establishing a causal link between subjective conscious experience and measurable neuronal activity. The present review focuses on the well-delimited issue of how an external or internal piece of information goes beyond nonconscious processing and gains access to conscious processing, a transition characterized by the existence of a reportable subjective experience. Converging neuroimaging and neurophysiological data, acquired during minimal experimental contrasts between conscious and nonconscious processing, point to objective neural measures of conscious access: late amplification of relevant sensory activity, long-distance cortico-cortical synchronization at beta and gamma frequencies, and "ignition" of a large-scale prefronto-parietal network. We compare these findings to current theoretical models of conscious processing, including the Global Neuronal Workspace (GNW) mod! el according to which conscious access occurs when incoming information is made globally available to multiple brain systems through a network of neurons with long-range axons densely distributed in prefrontal, parieto-temporal, and cingulate cortices. The clinical implications of these results for general anesthesia, coma, vegetative state, and schizophrenia are discussed.
• Development of a MR-Visible Compound for Tracing Neuroanatomical Connections In Vivo
  - Neuron (Cambridge Mass ) 70(2):229-243 (2011)
  Traditional studies of neuroanatomical connections require injection of tracer compounds into living brains, then histology of the postmortem tissue. Here, we describe and validate a compound that reveals neuronal connections in vivo, using MRI. The classic anatomical tracer CTB (cholera-toxin subunit-B) was conjugated with a gadolinium-chelate to form GdDOTA-CTB. GdDOTA-CTB was injected into the primary somatosensory cortex (S1) or the olfactory pathway of rats. High-resolution MR images were collected at a range of time points at 11.7T and 7T. The transported GdDOTA-CTB was visible for at least 1 month post-injection, clearing within 2 months. Control injections of non-conjugated GdDOTA into S1 were not transported and cleared within 1–2 days. Control injections of Gd-Albumin were not transported either, clearing within 7 days. These MR results were verified by classic immunohistochemical staining for CTB, in the same animals. The GdDOTA-CTB neuronal transport was ! target specific, monosynaptic, stable for several weeks, and reproducible.
• Doc2 Supports Spontaneous Synaptic Transmission by a Ca2+-Independent Mechanism
  - Neuron (Cambridge Mass ) 70(2):244-251 (2011)
  Two families of Ca2+-binding proteins have been proposed as Ca2+ sensors for spontaneous release: synaptotagmins and Doc2s, with the intriguing possibility that Doc2s may represent high-affinity Ca2+ sensors that are activated by deletion of synaptotagmins, thereby accounting for the increased spontaneous release in synaptotagmin-deficient synapses. Here, we use an shRNA-dependent quadruple knockdown of all four Ca2+-binding proteins of the Doc2 family to confirm that Doc2-deficient synapses exhibit a marked decrease in the frequency of spontaneous release events. Knockdown of Doc2s in synaptotagmin-1-deficient synapses, however, failed to reduce either the increased spontaneous release or the decreased evoked release of these synapses, suggesting that Doc2s do not constitute Ca2+ sensors for asynchronous release. Moreover, rescue experiments revealed that the decrease in spontaneous release induced by the Doc2 knockdown in wild-type synapses is fully reversed by mutan! t Doc2B lacking Ca2+-binding sites. Thus, our data suggest that Doc2s are modulators of spontaneous synaptic transmission that act by a Ca2+-independent mechanism.
• The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression
  - Neuron (Cambridge Mass ) 70(2):252-265 (2011)
  Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be acce! ssible to drug targeting.
• The Oriented Emergence of Axons from Retinal Ganglion Cells Is Directed by Laminin Contact In Vivo
  - Neuron (Cambridge Mass ) 70(2):266-280 (2011)
  How the site of axon emergence is specified during neural development is not understood. Previous studies disagree on the relative importance of intrinsic and extrinsic mechanisms. The axons of retinal ganglion cells (RGCs) emerge basally in vivo, yet because RGCs develop from polarized neuroepithelial cells within a polarized environment, disentangling intrinsic and extrinsic influences is a challenge. We use time-lapse imaging to demonstrate that Laminin acting directly on RGCs is necessary and sufficient to orient axon emergence in vivo. Laminin contact with the basal processes of newborn RGCs prevents the cells from entering a stochastic Stage 2 phase, directs the rapid accumulation of the early axonal marker Kif5c560-YFP, and leads to the formation of axonal growth cones. These results suggest that contact-mediated cues may be critical for the site of axon emergence and account for the differences in cellular behavior observed in vitro and in vivo. Video Abstract
• A Combinatorial Semaphorin Code Instructs the Initial Steps of Sensory Circuit Assembly in the Drosophila CNS
  - Neuron (Cambridge Mass ) 70(2):281-298 (2011)
  Longitudinal axon fascicles within the Drosophila embryonic CNS provide connections between body segments and are required for coordinated neural signaling along the anterior-posterior axis. We show here that establishment of select CNS longitudinal tracts and formation of precise mechanosensory afferent innervation to the same CNS region are coordinately regulated by the secreted semaphorins Sema-2a and Sema-2b. Both Sema-2a and Sema-2b utilize the same neuronal receptor, plexin B (PlexB), but serve distinct guidance functions. Localized Sema-2b attraction promotes the initial assembly of a subset of CNS longitudinal projections and subsequent targeting of chordotonal sensory afferent axons to these same longitudinal connectives, whereas broader Sema-2a repulsion serves to prevent aberrant innervation. In the absence of Sema-2b or PlexB, chordotonal afferent connectivity within the CNS is severely disrupted, resulting in specific larval behavioral deficits. These resu! lts reveal that distinct semaphorin-mediated guidance functions converge at PlexB and are critical for functional neural circuit assembly.
• Lateral Facilitation between Primary Mechanosensory Neurons Controls Nose Touch Perception in C. elegans
  - Neuron (Cambridge Mass ) 70(2):299-309 (2011)
  The nematode C. elegans senses head and nose touch using multiple classes of mechanoreceptor neurons that are electrically coupled through a network of gap junctions. Using in vivo neuroimaging, we have found that multidendritic nociceptors in the head respond to harsh touch throughout their receptive field but respond to gentle touch only at the tip of the nose. Whereas the harsh touch response depends solely on cell-autonomous mechanosensory channels, gentle nose touch responses require facilitation by additional nose touch mechanoreceptors, which couple electrically to the nociceptors in a hub-and-spoke gap junction network. Conversely, nociceptor activity indirectly facilitates activation of the nose touch neurons, demonstrating that information flow across the network is bidirectional. Thus, a simple gap-junction circuit acts as a coincidence detector that allows primary sensory neurons to integrate information from neighboring mechanoreceptors and generate somato! sensory perception.
• Molecular Motor KIF17 Is Fundamental for Memory and Learning via Differential Support of Synaptic NR2A/2B Levels
  - Neuron (Cambridge Mass ) 70(2):310-325 (2011)
  Kinesin superfamily motor protein 17 (KIF17) is a candidate transporter of N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B). Disruption of the murine kif17 gene inhibits NR2B transport, accompanied by decreased transcription of nr2b, resulting in a loss of synaptic NR2B. In kif17−/− hippocampal neurons, the NR2A level is also decreased because of accelerated ubiquitin-proteasome system-dependent degradation. Accordingly, NMDA receptor-mediated synaptic currents, early and late long-term potentiation, long-term depression, and CREB responses are attenuated in kif17−/− neurons, concomitant with a hippocampus-dependent memory impairment in knockout mice. In wild-type neurons, CREB is activated by synaptic inputs, which increase the levels of KIF17 and NR2B. Thus, KIF17 differentially maintains the levels of NR2A and NR2B, and, when synapses are stimulated, the NR2B/KIF17 complex is upregulated on demand through CREB activity. These KIF17-based mechanisms for! maintaining NR2A/2B levels could underlie multiple phases of memory processes in vivo.
• Calcium-Dependent Synaptic Vesicle Trafficking Underlies Indefatigable Release at the Hair Cell Afferent Fiber Synapse
  - Neuron (Cambridge Mass ) 70(2):326-338 (2011)
  Sensory hair cell ribbon synapses respond to graded stimulation in a linear, indefatigable manner, requiring that vesicle trafficking to synapses be rapid and nonrate-limiting. Real-time monitoring of vesicle fusion identified two release components. The first was saturable with both release rate and magnitude varying linearly with Ca2+, however the magnitude was too small to account for sustained afferent firing rates. A second superlinear release component required recruitment, in a Ca2+-dependent manner, of vesicles not in the immediate vicinity of the synapse. The superlinear component had a constant rate with its onset varying with Ca2+ load. High-speed Ca2+ imaging revealed a nonlinear increase in internal Ca2+ correlating with the superlinear capacitance change, implicating release of stored Ca2+ in driving vesicle recruitment. These data, supported by a mass action model, suggest sustained release at hair cell afferent fiber synapse is dictated by Ca2+-dependen! t vesicle recruitment from a reserve pool.
• mGluR5 and NMDA Receptors Drive the Experience- and Activity-Dependent NMDA Receptor NR2B to NR2A Subunit Switch
  - Neuron (Cambridge Mass ) 70(2):339-351 (2011)
  In cerebral cortex there is a developmental switch from NR2B- to NR2A-containing NMDA receptors (NMDARs) driven by activity and sensory experience. This subunit switch alters NMDAR function, influences synaptic plasticity, and its dysregulation is associated with neurological disorders. However, the mechanisms driving the subunit switch are not known. Here, we show in hippocampal CA1 pyramidal neurons that the NR2B to NR2A switch driven acutely by activity requires activation of NMDARs and mGluR5, involves PLC, Ca2+ release from IP3R-dependent stores, and PKC activity. In mGluR5 knockout mice the developmental NR2B-NR2A switch in CA1 is deficient. Moreover, in visual cortex of mGluR5 knockout mice, the NR2B-NR2A switch evoked in vivo by visual experience is absent. Thus, we establish that mGluR5 and NMDARs are required for the activity-dependent NR2B-NR2A switch and play a critical role in experience-dependent regulation of NMDAR subunit composition in vivo.
• fMRI of the Face-Processing Network in the Ventral Temporal Lobe of Awake and Anesthetized Macaques
  - Neuron (Cambridge Mass ) 70(2):352-362 (2011)
  The primate brain features specialized areas devoted to processing of faces, which human imaging studies localized in the superior temporal sulcus (STS) and ventral temporal cortex. Studies in macaque monkeys, in contrast, revealed face selectivity predominantly in the STS. While this discrepancy could result from a true species difference, it may simply be the consequence of technical difficulties in obtaining high-quality MR images from the ventral temporal lobe. By using an optimized fMRI protocol we here report face-selective areas in ventral TE, the parahippocampal cortex, the entorhinal cortex, and the hippocampus of awake macaques, in addition to those already known in the STS. Notably, the face-selective activation of these memory-related areas was observed although the animals were passively viewing and it was preserved even under anesthesia. These results point to similarly extensive cortical networks for face processing in humans and monkeys and highlight po! tential homologs of the human fusiform face area.
• Multisensory Mechanisms in Temporo-Parietal Cortex Support Self-Location and First-Person Perspective
  - Neuron (Cambridge Mass ) 70(2):363-374 (2011)
  Self-consciousness has mostly been approached by philosophical enquiry and not by empirical neuroscientific study, leading to an overabundance of diverging theories and an absence of data-driven theories. Using robotic technology, we achieved specific bodily conflicts and induced predictable changes in a fundamental aspect of self-consciousness by altering where healthy subjects experienced themselves to be (self-location). Functional magnetic resonance imaging revealed that temporo-parietal junction (TPJ) activity reflected experimental changes in self-location that also depended on the first-person perspective due to visuo-tactile and visuo-vestibular conflicts. Moreover, in a large lesion analysis study of neurological patients with a well-defined state of abnormal self-location, brain damage was also localized at TPJ, providing causal evidence that TPJ encodes self-location. Our findings reveal that multisensory integration at the TPJ reflects one of the most funda! mental subjective feelings of humans: the feeling of being an entity localized at a position in space and perceiving the world from this position and perspective.
• Strength of Response Suppression to Distracter Stimuli Determines Attentional-Filtering Performance in Primate Prefrontal Neurons
  - Neuron (Cambridge Mass ) 70(2):375 (2011)