Hot off the presses! Jul 14 Neuron

The Jul 14 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:

• The Axon's Balancing Act: cis- and trans-Interactions between Ephs and Ephrins
  - Neuron 71(1):1-3 (2011)
  Ephrin ligands are known to be coexpressed with Eph receptors in certain populations of axons. In this issue of Neuron, Kao and Kania demonstrate the importance of ephrin/Eph cis-interaction for correct pathway selection by spinal motor axons in vivo.
• Leptin Grows Up and Gets a Neural Network
  - Neuron 71(1):4-6 (2011)
  Studies seeking a dominant site of action for the hormone leptin have focused on leptin receptor-expressing neuropeptidergic neurons. In this issue, Vong et al. show that leptin regulates energy homeostasis predominantly via a distributed network of GABAergic neurons.
• Timing Is Everything, Even for Cholinergic Control
  - Neuron 71(1):6-8 (2011)
  Synaptic plasticity is widely considered to be a cellular mechanism underlying learning and memory. In this issue of Neuron, Gu and Yakel show that the precise timing of a single cholinergic pulse of activity can determine whether plasticity will occur at a glutamatergic synapse and confer long-term potentiation versus depression.
• Optogenetics in Neural Systems
  - Neuron 71(1):9-34 (2011)
  Both observational and perturbational technologies are essential for advancing the understanding of brain function and dysfunction. But while observational techniques have greatly advanced in the last century, techniques for perturbation that are matched to the speed and heterogeneity of neural systems have lagged behind. The technology of optogenetics represents a step toward addressing this disparity. Reliable and targetable single-component tools (which encompass both light sensation and effector function within a single protein) have enabled versatile new classes of investigation in the study of neural systems. Here we provide a primer on the application of optogenetics in neuroscience, focusing on the single-component tools and highlighting important problems, challenges, and technical considerations.
• Selective Neuronal Vulnerability in Neurodegenerative Diseases: from Stressor Thresholds to Degeneration
  - Neuron 71(1):35-48 (2011)
  Neurodegenerative diseases selectively target subpopulations of neurons, leading to the progressive failure of defined brain systems, but the basis of such selective neuronal vulnerability has remained elusive. Here, we discuss how a stressor-threshold model of how particular neurons and circuits are selectively vulnerable to disease may underly the etiology of familial and sporadic forms of diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS. According to this model, the intrinsic vulnerabilities of neuronal subpopulations to stressors and specific disease-related misfolding proteins determine neuronal morbidity. Neurodegenerative diseases then involve specific combinations of genetic predispositions and environmental stressors, triggering increasing age-related stress and proteostasis dysfunction in affected vulnerable neurons. Damage to vasculature, immune system, and local glial cells mediates environmental stress, which could drive disease at all stag! es.
• The Functional Neuroanatomy of Object Agnosia: A Case Study
  - Neuron 71(1):49-60 (2011)
  Cortical reorganization of visual and object representations following neural injury was examined using fMRI and behavioral investigations. We probed the visual responsivity of the ventral visual cortex of an agnosic patient who was impaired at object recognition following a lesion to the right lateral fusiform gyrus. In both hemispheres, retinotopic mapping revealed typical topographic organization and visual activation of early visual cortex. However, visual responses, object-related, and -selective responses were reduced in regions immediately surrounding the lesion in the right hemisphere, and also, surprisingly, in corresponding locations in the structurally intact left hemisphere. In contrast, hV4 of the right hemisphere showed expanded response properties. These findings indicate that the right lateral fusiform gyrus is critically involved in object recognition and that an impairment to this region has widespread consequences for remote parts of cortex. Finally,! functional neural plasticity is possible even when a cortical lesion is sustained in adulthood. 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 (8818 K)
• Ank3-Dependent SVZ Niche Assembly Is Required for the Continued Production of New Neurons
  - Neuron 71(1):61-75 (2011)
  The rodent subventricular/subependymal zone (SVZ/SEZ) houses neural stem cells (NSCs) that generate olfactory bulb interneurons. It is unclear how the SVZ environment sustains neuronal production into adulthood. We discovered that the adapter molecule Ankyrin-3 (Ank3) is specifically upregulated in ventricular progenitors destined to become ependymal cells, but not in NSCs, and is required for SVZ niche assembly through progenitor lateral adhesion. Furthermore, we found that Ank3 expression is controlled by Foxj1, a transcriptional regulator of multicilia formation, and genetic deletion of this pathway led to complete loss of SVZ niche structure. Interestingly, radial glia continued to transition into postnatal NSCs without this niche. However, inducible deletion of Foxj1-Ank3 from mature SVZ ependyma resulted in dramatic depletion of neurogenesis. Targeting a pathway regulating ependymal organization/assembly and showing its requirement for new neuron production, our ! results have important implications for environmental control of adult neurogenesis and harvesting NSCs for replacement therapy.
• Ephrin-Mediated cis-Attenuation of Eph Receptor Signaling Is Essential for Spinal Motor Axon Guidance
  - Neuron 71(1):76-91 (2011)
  Axon guidance receptors guide neuronal growth cones by binding in trans to axon guidance ligands in the developing nervous system. Some ligands are coexpressed in cis with their receptors, raising the question of the relative contribution of cis and trans interactions to axon guidance. Spinal motor axons use Eph receptors to select a limb trajectory in response to trans ephrins, while expressing ephrins in cis. We show that changes in motor neuron ephrin expression result in trajectory selection defects mirrored by changes in growth cone sensitivity to ephrins in vitro, arguing for ephrin cis-attenuation of Eph function. Furthermore, the relative contribution of trans-signaling and cis-attenuation is influenced by the subcellular distribution of ephrins to membrane patches containing Eph receptors. Thus, growth cone ephrins are essential for axon guidance in vivo and the balance between cis and trans modes of axon guidance ligand-receptor interaction contributes to the! diversity of axon guidance signaling responses.
• A Neuropeptide-Mediated Stretch Response Links Muscle Contraction to Changes in Neurotransmitter Release
  - Neuron 71(1):92-102 (2011)
  Although Caenorhabditis elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of proneuropeptides, by mutations inactivating a single proneuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest ! that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion.
• The Immunoglobulin Super Family Protein RIG-3 Prevents Synaptic Potentiation and Regulates Wnt Signaling
  - Neuron 71(1):103-116 (2011)
  Cell surface Ig superfamily proteins (IgSF) have been implicated in several aspects of neuron development and function. Here, we describe the function of a Caenorhabditis elegans IgSF protein, RIG-3. Mutants lacking RIG-3 have an exaggerated paralytic response to a cholinesterase inhibitor, aldicarb. Although RIG-3 is expressed in motor neurons, heightened drug responsiveness was caused by an aldicarb-induced increase in muscle ACR-16 acetylcholine receptor (AChR) abundance, and a corresponding potentiation of postsynaptic responses at neuromuscular junctions. Mutants lacking RIG-3 also had defects in the anteroposterior polarity of the ALM mechanosensory neurons. The effects of RIG-3 on synaptic transmission and ALM polarity were both mediated by changes in Wnt signaling, and in particular by inhibiting CAM-1, a Ror-type receptor tyrosine kinase that binds Wnt ligands. These results identify RIG-3 as a regulator of Wnt signaling, and suggest that RIG-3 has an anti-pla! sticity function that prevents activity-induced changes in postsynaptic receptor fields.
• Nuclear Calcium-VEGFD Signaling Controls Maintenance of Dendrite Arborization Necessary for Memory Formation
  - Neuron 71(1):117-130 (2011)
  The role of neuronal dendrites is to receive and process synaptic inputs. The geometry of the dendritic arbor can undergo neuronal activity-dependent changes that may impact the cognitive abilities of the organism. Here we show that vascular endothelial growth factor D (VEGFD), commonly known as an angiogenic mitogen, controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus. VEGFD expression is dependent upon basal neuronal activity and requires nuclear calcium-calmodulin-dependent protein kinase IV (CaMKIV) signaling. Suppression of VEGFD expression in the mouse hippocampus by RNA interference causes memory impairments. Thus, nuclear calcium-VEGFD signaling mediates the effect of neuronal activity on the maintenance of dendritic arbors in the adult hippocampus and is required for cognitive functioning. These results suggest that caution be employed in the clinical use of blockers of VEGFD signaling f! or antiangiogenic cancer therapy.
• S-Nitrosylation and S-Palmitoylation Reciprocally Regulate Synaptic Targeting of PSD-95
  - Neuron 71(1):131-141 (2011)
  PSD-95, a principal scaffolding component of the postsynaptic density, is targeted to synapses by palmitoylation, where it couples NMDA receptor stimulation to production of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS). Here, we show that PSD-95 is physiologically S-nitrosylated. We identify cysteines 3 and 5, which are palmitoylated, as sites of nitrosylation, suggesting a competition between these two modifications. In support of this hypothesis, physiologically produced NO inhibits PSD-95 palmitoylation in granule cells of the cerebellum, decreasing the number of PSD-95 clusters at synaptic sites. Further, decreased palmitoylation, as seen in heterologous cells treated with 2-bromopalmitate or in ZDHHC8 knockout mice deficient in a PSD-95 palmitoyltransferase, results in increased PSD-95 nitrosylation. These data support a model in which NMDA-mediated production of NO regulates targeting of PSD-95 to synapses via mutually competitive cysteine modificat! ions. Thus, differential modification of cysteines may represent a general paradigm in signal transduction.
• Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
  - Neuron 71(1):142-154 (2011)
  Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin actio! n on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.
• Timing-Dependent Septal Cholinergic Induction of Dynamic Hippocampal Synaptic Plasticity
  - Neuron 71(1):155-165 (2011)
  Cholinergic modulation of hippocampal synaptic plasticity has been studied extensively by applying receptor agonists or blockers; however, the effect of rapid physiological cholinergic stimuli on plasticity is largely unknown. Here, we report that septal cholinergic input, activated either by electrical stimulation or via an optogenetic approach, induced different types of hippocampal Schaffer collateral (SC) to CA1 synaptic plasticity, depending on the timing of cholinergic input relative to the SC input. When the cholinergic input was activated 100 or 10 ms prior to SC stimulation, it resulted in α7 nAChR-dependent long-term potentiation (LTP) or short-term depression, respectively. When the cholinergic stimulation was delayed until 10 ms after the SC stimulation, a muscarinic AChR-dependent LTP was induced. Moreover, these various forms of plasticity were disrupted by Aβ exposure. These results have revealed the remarkable temporal precision of cholinergic functio! ns, providing a novel mechanism for information processing in cholinergic-dependent higher cognitive functions.
• Delayed-Rectifier K Channels Contribute to Contrast Adaptation in Mammalian Retinal Ganglion Cells
  - Neuron 71(1):166-179 (2011)
  Retinal ganglion cells adapt by reducing their sensitivity during periods of high contrast. Contrast adaptation in the firing response depends on both presynaptic and intrinsic mechanisms. Here, we investigated intrinsic mechanisms for contrast adaptation in OFF Alpha ganglion cells in the in vitro guinea pig retina. Using either visual stimulation or current injection, we show that brief depolarization evoked spiking and suppressed firing during subsequent depolarization. The suppression could be explained by Na channel inactivation, as shown in salamander cells. However, brief hyperpolarization in the physiological range (5–10 mV) also suppressed firing during subsequent depolarization. This suppression was selectively sensitive to blockers of delayed-rectifier K channels (KDR). In somatic membrane patches, we observed tetraethylammonium-sensitive KDR currents that activated near −25 mV. Recovery from inactivation occurred at potentials hyperpolarized to Vrest. B! rief periods of hyperpolarization apparently remove KDR inactivation and thereby increase the channel pool available to suppress excitability during subsequent depolarization.
• Multiple Clusters of Release Sites Formed by Individual Thalamic Afferents onto Cortical Interneurons Ensure Reliable Transmission
  - Neuron 71(1):180-194 (2011)
  Thalamic afferents supply the cortex with sensory information by contacting both excitatory neurons and inhibitory interneurons. Interestingly, thalamic contacts with interneurons constitute such a powerful synapse that even one afferent can fire interneurons, thereby driving feedforward inhibition. However, the spatial representation of this potent synapse on interneuron dendrites is poorly understood. Using Ca imaging and electron microscopy we show that an individual thalamic afferent forms multiple contacts with the interneuronal proximal dendritic arbor, preferentially near branch points. More contacts are correlated with larger amplitude synaptic responses. Each contact, consisting of a single bouton, can release up to seven vesicles simultaneously, resulting in graded and reliable Ca transients. Computational modeling indicates that the release of multiple vesicles at each contact minimally reduces the efficiency of the thalamic afferent in exciting the interneu! ron. This strategy preserves the spatial representation of thalamocortical inputs across the dendritic arbor over a wide range of release conditions.
• Solving the Autism Puzzle a Few Pieces at a Time
  - Neuron 71(1):195 (2011)