Hot off the presses! Aug 13 Neuron

The Aug 13 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:

• IGF-1: Elixir for Motor Neuron Diseases
  Papanikolaou T Ellerby LM - Neuron 63(3):277-278 (2009)
  Modulation of testosterone levels is a therapeutic approach for spinal and bulbar muscular atrophy (SBMA), a polyglutamine disorder that affects the motor neurons. The article by Palazzolo et al. in this issue of Neuron provides compelling evidence that the expression of insulin growth hormone is a potential therapeutic for SBMA.
• Too Fat to Fly? New Brain Circuits Regulate Obesity in Drosophila
  Kaun KR Heberlein U - Neuron 63(3):279-281 (2009)
  In mammals, fat store levels are regulated by brain centers that control food intake and metabolism. A new study by Al-Anzi and colleagues in this issue of Neuron identifies neurons with similar functions in Drosophila, further establishing the fly as a legitimate model to study obesity.
• The Pre/Post LTP Debate
  Lisman JE - Neuron 63(3):281-284 (2009)
  The pre/post debate involves the question of whether long-term potentiation (LTP) is mediated by enhancement of release, enhancement of postsynaptic receptors, or both. Recent papers have presented evidence for purely postsynaptic or purely presynaptic changes, and a paper by Ahmed and Siegelbam (in this issue of Neuron) suggests a mechanism by which release is enhanced. This debate is increasingly constrained by technical advances that allow central synapses to be studied with increasing precision. A possible of way of reconciling conflicting evidence is suggested.
• A Nonvisual Look at the Functional Organization of Visual Cortex
  Peelen MV Kastner S - Neuron 63(3):284-286 (2009)
  In this issue of Neuron, Mahon et al. show that the ventral visual cortex of congenitally blind individuals, who have never experienced the visual world, has an object-category organization similar to that found in sighted individuals. Here, we discuss the implications of this finding for our understanding of the "visual" cortex.
• The Role of Apolipoprotein E in Alzheimer's Disease
  Kim J Basak JM Holtzman DM - Neuron 63(3):287-303 (2009)
  The 4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Aβ aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
• Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele
  Kim JC Cook MN Carey MR Shen C Regehr WG Dymecki SM - Neuron 63(3):305-315 (2009)
  Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors. Among various test populations, we applied RC::PFtox to silence serotonergic neurons, en masse or a subset defined combinatorially. Of the behavioral phenotypes observed upon en masse serotonergic silencing, only one mapped to the combinatorially defined subset. These findings provide eviden! ce for separability by genetic lineage of serotonin-modulated behaviors; collectively, these findings demonstrate broad utility of RC::PFtox for dissecting neuron functions.
• Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy
  Palazzolo I Stack C Kong L Musaro A Adachi H Katsuno M Sobue G Taylor JP Sumner CJ Fischbeck KH Pennuto M - Neuron 63(3):316-328 (2009)
  Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target ! tissue for therapeutic intervention in SBMA.
• Obesity-Blocking Neurons in Drosophila
  Al-Anzi B Sapin V Waters C Zinn K Wyman RJ Benzer S - Neuron 63(3):329-341 (2009)
  In mammals, fat store levels are communicated by leptin and insulin signaling to brain centers that regulate food intake and metabolism. By using transgenic manipulation of neural activity, we report the isolation of two distinct neuronal populations in flies that perform a similar function, the c673a-Gal4 and fruitless-Gal4 neurons. When either of these neuronal groups is silenced, fat store levels increase. This change is mediated through an increase in food intake and altered metabolism in c673a-Gal4-silenced flies, while silencing fruitless-Gal4 neurons alters only metabolism. Hyperactivation of either neuronal group causes depletion of fat stores by increasing metabolic rate and decreasing fatty acid synthesis. Altering the activities of these neurons causes changes in expression of genes known to regulate fat utilization. Our results show that the fly brain measures fat store levels and can induce changes in food intake and metabolism to maintain them within norm! al limits.
• Downregulation of NR3A-Containing NMDARs Is Required for Synapse Maturation and Memory Consolidation
  Roberts AC Díez-García J Rodriguiz RM López IP Luján R Martínez-Turrillas R Picó E Henson MA Bernardo DR Jarrett TM Clendeninn DJ López-Mascaraque L Feng G Lo DC Wesseling JF Wetsel WC Philpot BD Pérez-Otaño I - Neuron 63(3):342-356 (2009)
  NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses! and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.
• A Role for SNAP25 in Internalization of Kainate Receptors and Synaptic Plasticity
  Selak S Paternain AV Aller IM Picó E Rivera R Lerma J - Neuron 63(3):357-371 (2009)
  Regulation of surface insertion and internalization of AMPA and NMDA receptors has emerged as a key mechanism for the control of synaptic strength. Regulatory elements for synaptic kainate receptors (KARs) are, however, largely undetermined. We have found that SNAP25 is critical for the synaptic removal of KARs, acting via GluK5 (i.e., KA2) subunits. SNAP25 coimmunoprecipitates with protein complexes containing PICK1, GRIP1, and GluK5 and colocalizes with GluK5 in both hippocampal neurons and transfected HEK293 cells. In hippocampal slices, purified SNAP25 antibodies and blocking peptides caused a GluK5-dependent run-up of KARs-mediated EPSC (EPSCKAR) recorded from CA3 pyramidal neurons when included in the patch pipette and prevented activity-dependent long-term depression of EPSCKAR. As EPSCKAR LTD, SNAP25/PICK1/GluK5 interactions are dynamically regulated by PKC.
• Recruitment of N-Type Ca2+ Channels during LTP Enhances Low Release Efficacy of Hippocampal CA1 Perforant Path Synapses
  Ahmed MS Siegelbaum SA - Neuron 63(3):372-385 (2009)
  The entorhinal cortex provides both direct and indirect inputs to hippocampal CA1 neurons through the perforant path and Schaffer collateral synapses, respectively. Using both two-photon imaging of synaptic vesicle cycling and electrophysiological recordings, we found that the efficacy of transmitter release at perforant path synapses is lower than at Schaffer collateral inputs. This difference is due to the greater contribution to release by presynaptic N-type voltage-gated Ca2+ channels at the Schaffer collateral than perforant path synapses. Induction of long-term potentiation that depends on activation of NMDA receptors and L-type voltage-gated Ca2+ channels enhances the low efficacy of release at perforant path synapses by increasing the contribution of N-type channels to exocytosis. This represents a previously uncharacterized presynaptic mechanism for fine-tuning release properties of distinct classes of synapses onto a common postsynaptic neuron and for regulat! ing synaptic function during long-term synaptic plasticity.
• Serial, Covert Shifts of Attention during Visual Search Are Reflected by the Frontal Eye Fields and Correlated with Population Oscillations
  Buschman TJ Miller EK - Neuron 63(3):386-396 (2009)
  Attention regulates the flood of sensory information into a manageable stream, and so understanding how attention is controlled is central to understanding cognition. Competing theories suggest visual search involves serial and/or parallel allocation of attention, but there is little direct, neural evidence for either mechanism. Two monkeys were trained to covertly search an array for a target stimulus under visual search (endogenous) and pop-out (exogenous) conditions. Here, we present neural evidence in the frontal eye fields (FEF) for serial, covert shifts of attention during search but not pop-out. Furthermore, attention shifts reflected in FEF spiking activity were correlated with 18–34 Hz oscillations in the local field potential, suggesting a "clocking" signal. This provides direct neural evidence that primates can spontaneously adopt a serial search strategy and that these serial covert shifts of attention are directed by the FEF. It also suggests that ne! uron population oscillations may regulate the timing of cognitive processing.
• Category-Specific Organization in the Human Brain Does Not Require Visual Experience
  Mahon BZ Anzellotti S Schwarzbach J Zampini M Caramazza A - Neuron 63(3):397-405 (2009)
  Distinct regions within the ventral visual pathway show neural specialization for nonliving and living stimuli (e.g., tools, houses versus animals, faces). The causes of these category preferences are widely debated. Using functional magnetic resonance imaging, we find that the same regions of the ventral stream that show category preferences for nonliving stimuli and animals in sighted adults show the same category preferences in adults who are blind since birth. Both blind and sighted participants had larger blood oxygen-level dependent (BOLD) responses in the medial fusiform gyrus for nonliving stimuli compared to animal stimuli and differential BOLD responses in lateral occipital cortex for animal stimuli compared to nonliving stimuli. These findings demonstrate that the medial-to-lateral bias by conceptual domain in the ventral visual pathway does not require visual experience in order to develop and suggest the operation of innately determined domain-specific con! straints on the organization of object knowledge.
• Motor Learning Is Optimally Tuned to the Properties of Motor Noise
  van Beers RJ - Neuron 63(3):406-417 (2009)
  In motor learning, our brain uses movement errors to adjust planning of future movements. This process has traditionally been studied by examining how motor planning is adjusted in response to visuomotor or dynamic perturbations. Here, I show that the learning strategy can be better identified from the statistics of movements made in the absence of perturbations. The strategy identified this way differs from the learning mechanism assumed in mainstream models for motor learning. Crucial for this strategy is that motor noise arises partly centrally, in movement planning, and partly peripherally, in movement execution. Corrections are made by modification of central planning signals from the previous movement, which include the effects of planning but not execution noise. The size of the corrections is such that the movement variability is minimized. This physiologically plausible strategy is optimally tuned to the properties of motor noise, and likely underlies learning! in many motor tasks.