Hot off the presses! Dec 09 Neuron

The Dec 09 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:

• Complexin: Does It Deserve Its Name?
  - Neuron (Cambridge Mass ) 68(5):803-806 (2010)
  Knockout and other perturbations of complexins have provided important insights and elicited controversies about their role in neurotransmitter release. New work by Yang et al. in this issue of Neuron adds important detail and complexity to existing concepts—particularly on the nature of a Ca2+-dependent complexin-synaptotagmin switch for the triggering of exocytosis. But it also provokes thoughts about alternative interpretations, which might result in a simpler model of complexin function.
• Unloading Intracellular Calcium Stores Reveals Regionally Specific Functions
  - Neuron (Cambridge Mass ) 68(5):806-808 (2010)
  Neuronal excitability can be modulated by release of intracellular calcium but the impact of calcium store depletion on intrinsic neuronal properties is unknown. In this issue of Neuron, Narayanan et al. describe an intrinsic plasticity that is depletion induced, is regionally restricted, and may protect neurons from pathological alterations in calcium signaling.
• Cholinergic Signaling through Synaptic SK Channels: It's a Protein Kinase but Which One?
  - Neuron (Cambridge Mass ) 68(5):809-811 (2010)
  Cholinergic signaling modulates synaptic responses and influences cognition. In this issue of Neuron, two groups (Buchanan et al. and Giessel and Sabatini) present evidence that cholinergic signaling enhances postsynaptic responses in CA1 neurons by decreasing synaptic SK channel activity. However, they come to different conclusions about the protein kinases involved in this process.
• Capturing VCP: Another Molecular Piece in the ALS Jigsaw Puzzle
  - Neuron (Cambridge Mass ) 68(5):812-814 (2010)
  TDP-43 mislocalization and aggregation are implicated in the pathogenesis of ALS and FTLD-U. Valosin containing protein (VCP) mutations also lead to TDP-43 deposition, resulting in Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). In this issue of Neuron, Johnson et al. used whole-exome capture to identify VCP mutations in familial ALS. This extends the VCP phenotype to include motor neuron degeneration and provides another molecular tool to explore neurodegeneration disease mechanisms underlying the TDP-43 proteinopathies.
• Dopamine in Motivational Control: Rewarding, Aversive, and Alerting
  - Neuron (Cambridge Mass ) 68(5):815-834 (2010)
  Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways! for value, salience, and alerting cooperate to support adaptive behavior.
• The Medial Temporal Lobe Supports Conceptual Implicit Memory
  - Neuron (Cambridge Mass ) 68(5):835-842 (2010)
  The medial temporal lobe (MTL) is generally thought to be critical for explicit, but not implicit, memory. Here, we demonstrate that the perirhinal cortex (PRc), within the MTL, plays a role in conceptually-driven implicit memory. Amnesic patients with MTL lesions that converged on the left PRc exhibited deficits on two conceptual implicit tasks (i.e., exemplar generation and semantic decision). A separate functional magnetic resonance imaging (fMRI) study in healthy subjects indicated that PRc activation during encoding of words was predictive of subsequent exemplar generation. Moreover, across subjects, the magnitude of the fMRI and behavioral conceptual priming effects were directly related. Additionally, the PRc region implicated in the fMRI study was the same region of maximal lesion overlap in the patients with impaired conceptual priming. These patient and imaging results converge to suggest that the PRc plays a critical role in conceptual implicit memory, and p! ossibly conceptual processing in general.
• Superresolution Imaging of Chemical Synapses in the Brain
  - Neuron (Cambridge Mass ) 68(5):843-856 (2010)
  Determination of the molecular architecture of synapses requires nanoscopic image resolution and specific molecular recognition, a task that has so far defied many conventional imaging approaches. Here, we present a superresolution fluorescence imaging method to visualize the molecular architecture of synapses in the brain. Using multicolor, three-dimensional stochastic optical reconstruction microscopy, the distributions of synaptic proteins can be measured with nanometer precision. Furthermore, the wide-field, volumetric imaging method enables high-throughput, quantitative analysis of a large number of synapses from different brain regions. To demonstrate the capabilities of this approach, we have determined the organization of ten protein components of the presynaptic active zone and the postsynaptic density. Variations in synapse morphology, neurotransmitter receptor composition, and receptor distribution were observed both among synapses and across different brain! regions. Combination with optogenetics further allowed molecular events associated with synaptic plasticity to be resolved at the single-synapse level.
• Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
  - Neuron (Cambridge Mass ) 68(5):857-864 (2010)
  Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for 1%–2% of familial ALS, and provide evidence directly implicating d! efects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
• Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor
  - Neuron (Cambridge Mass ) 68(5):865-878 (2010)
  Deranged Ca2+ signaling and an accumulation of aberrant proteins cause endoplasmic reticulum (ER) stress, which is a hallmark of cell death implicated in many neurodegenerative diseases. However, the underlying mechanisms are elusive. Here, we report that dysfunction of an ER-resident Ca2+ channel, inositol 1,4,5-trisphosphate receptor (IP3R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP3R (IP3R1) resulted in neuronal vulnerability to ER stress in vivo, and IP3R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP3R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP3R1 dysfunction through an impaired IP3R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP3R1 senses ER stress through GRP78 to alter the Ca2+ signal to promote neuronal cell death! implicated in neurodegenerative diseases.
• The Drosophila miR-310 Cluster Negatively Regulates Synaptic Strength at the Neuromuscular Junction
  - Neuron (Cambridge Mass ) 68(5):879-893 (2010)
  Emerging data implicate microRNAs (miRNAs) in the regulation of synaptic structure and function, but we know little about their role in the regulation of neurotransmission in presynaptic neurons. Here, we demonstrate that the miR-310–313 cluster is required for normal synaptic transmission at the Drosophila larval neuromuscular junction. Loss of miR-310–313 cluster leads to a significant enhancement of neurotransmitter release, which can be rescued with temporally restricted expression of mir-310–313 in larval presynaptic neurons. Kinesin family member, Khc-73 is a functional target for miR-310–313 as its expression is increased in mir-310–313 mutants and reducing it restores normal synaptic function. Cluster mutants show an increase in the active zone protein Bruchpilot accompanied by an increase in electron dense T bars. Finally, we show that repression of Khc-73 by miR-310–313 cluster influences the establishment of normal synaptic homeostasis. Our findi! ngs establish a role for miRNAs in the regulation of neurotransmitter release.
• SynCAM 1 Adhesion Dynamically Regulates Synapse Number and Impacts Plasticity and Learning
  - Neuron (Cambridge Mass ) 68(5):894-906 (2010)
  Synaptogenesis is required for wiring neuronal circuits in the developing brain and continues to remodel adult networks. However, the molecules organizing synapse development and maintenance in vivo remain incompletely understood. We now demonstrate that the immunoglobulin adhesion molecule SynCAM 1 dynamically alters synapse number and plasticity. Overexpression of SynCAM 1 in transgenic mice promotes excitatory synapse number, while loss of SynCAM 1 results in fewer excitatory synapses. By turning off SynCAM 1 overexpression in transgenic brains, we show that it maintains the newly induced synapses. SynCAM 1 also functions at mature synapses to alter their plasticity by regulating long-term depression. Consistent with these effects on neuronal connectivity, SynCAM 1 expression affects spatial learning, with knock-out mice learning better. The reciprocal effects of increased SynCAM 1 expression and loss reveal that this adhesion molecule contributes to the regulation ! of synapse number and plasticity, and impacts how neuronal networks undergo activity-dependent changes.
• Complexin Clamps Asynchronous Release by Blocking a Secondary Ca2+ Sensor via Its Accessory α Helix
  - Neuron (Cambridge Mass ) 68(5):907-920 (2010)
  Complexin activates and clamps neurotransmitter release; impairing complexin function decreases synchronous, but increases spontaneous and asynchronous synaptic vesicle exocytosis. Here, we show that complexin—different from the Ca2+ sensor synaptotagmin-1—activates synchronous exocytosis by promoting synaptic vesicle priming, but clamps spontaneous and asynchronous exocytosis—similar to synaptotagmin-1—by blocking a secondary Ca2+ sensor. Activation and clamping functions of complexin depend on distinct, autonomously acting sequences, namely its N-terminal region and accessory α helix, respectively. Mutations designed to test whether the accessory α helix of complexin clamps exocytosis by inserting into SNARE-complexes support this hypothesis, suggesting that the accessory α helix blocks completion of trans-SNARE-complex assembly until Ca2+ binding to synaptotagmin relieves this block. Moreover, a juxtamembranous mutation in the SNARE-protein synaptobrevin-! 2, which presumably impairs force transfer from nascent trans-SNARE complexes onto fusing membranes, also unclamps spontaneous fusion by disinhibiting a secondary Ca2+ sensor. Thus, complexin performs mechanistically distinct activation and clamping functions that operate in conjunction with synaptotagmin-1 by controlling trans-SNARE-complex assembly.
• Calcium Store Depletion Induces Persistent Perisomatic Increases in the Functional Density of h Channels in Hippocampal Pyramidal Neurons
  - Neuron (Cambridge Mass ) 68(5):921-935 (2010)
  The regulation of intracellular calcium by the endoplasmic reticulum (ER) plays a critical role in neuronal function. While the consequences associated with depleting calcium from the ER have been studied in multiple systems, it is not known whether the intrinsic properties of a neuron change in response to such perturbations. In this study, we demonstrate that the depletion of calcium from the ER of hippocampal CA1 pyramidal neurons induces a persistent, perisomatic increase in the density of functional h channels resulting in a reduction in intrinsic excitability and an increase in the optimal response frequency. This form of intrinsic plasticity is dependent on the elevation of cytoplasmic calcium, inositol triphosphate receptors, store-operated calcium channels, and the protein kinase A pathway. We postulate that this form of depletion-induced intrinsic plasticity is a neuroprotective mechanism that reduces excitability after depletion of calcium stores triggered t! hrough altered network activity during pathological conditions.
• M1 Muscarinic Receptors Boost Synaptic Potentials and Calcium Influx in Dendritic Spines by Inhibiting Postsynaptic SK Channels
  - Neuron (Cambridge Mass ) 68(5):936-947 (2010)
  Acetylcholine release and activation of muscarinic cholinergic receptors (mAChRs) enhance synaptic plasticity in vitro and cognition and memory in vivo. Within the hippocampus, mAChRs promote NMDA-type glutamate receptor-dependent forms of long-term potentiation. Here, we use calcium (Ca) imaging combined with two-photon laser glutamate uncaging at apical spines of CA1 pyramidal neurons to examine postsynaptic mechanisms of muscarinic modulation of glutamatergic transmission. Uncaging-evoked excitatory postsynaptic potentials and Ca transients are increased by muscarinic stimulation; however, this is not due to direct modulation of glutamate receptors. Instead, mAChRs modulate a negative feedback loop in spines that normally suppresses synaptic signals. mAChR activation reduces the Ca sensitivity of small conductance Ca-activated potassium (SK) channels that are found in the spine, resulting in increased synaptic potentials and Ca transients. These effects are mediated! by M1-type muscarinic receptors and occur in a casein kinase-2-dependent manner. Thus, muscarinic modulation regulates synaptic transmission by tuning the activity of nonglutamatergic postsynaptic ion channels.
• Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors Is Mediated by Inhibition of SK Channels
  - Neuron (Cambridge Mass ) 68(5):948-963 (2010)
  Muscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M1 receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M1 receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M1 receptor activation, indicating this is the mechanism for LTP facilitation. M1 receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M1 r! eceptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.
• Drosophila Pacemaker Neurons Require G Protein Signaling and GABAergic Inputs to Generate Twenty-Four Hour Behavioral Rhythms
  - Neuron (Cambridge Mass ) 68(5):964-977 (2010)
  Intercellular signaling is important for accurate circadian rhythms. In Drosophila, the small ventral lateral neurons (s-LNvs) are the dominant pacemaker neurons and set the pace of most other clock neurons in constant darkness. Here we show that two distinct G protein signaling pathways are required in LNvs for 24 hr rhythms. Reducing signaling in LNvs via the G alpha subunit Gs, which signals via cAMP, or via the G alpha subunit Go, which we show signals via Phospholipase 21c, lengthens the period of behavioral rhythms. In contrast, constitutive Gs or Go signaling makes most flies arrhythmic. Using dissociated LNvs in culture, we found that Go and the metabotropic GABAB-R3 receptor are required for the inhibitory effects of GABA on LNvs and that reduced GABAB-R3 expression in vivo lengthens period. Although no clock neurons produce GABA, hyperexciting GABAergic neurons disrupts behavioral rhythms and s-LNv molecular clocks. Therefore, s-LNvs require GABAergic inputs ! for 24 hr rhythms.
• Spiral Wave Dynamics in Neocortex
  - Neuron (Cambridge Mass ) 68(5):978-990 (2010)
  Although spiral waves are ubiquitous features of nature and have been observed in many biological systems, their existence and potential function in mammalian cerebral cortex remain uncertain. Using voltage-sensitive dye imaging, we found that spiral waves occur frequently in the neocortex in vivo, both during pharmacologically induced oscillations and during sleep-like states. While their life span is limited, spiral waves can modify ongoing cortical activity by influencing oscillation frequencies and spatial coherence and by reducing amplitude in the area surrounding the spiral phase singularity. During sleep-like states, the rate of occurrence of spiral waves varies greatly depending on brain states. These results support the hypothesis that spiral waves, as an emergent activity pattern, can organize and modulate cortical population activity on the mesoscopic scale and may contribute to both normal cortical processing and to pathological patterns of activity such as! those found in epilepsy.
• Neural Correlates of Variations in Event Processing during Learning in Central Nucleus of Amygdala
  - Neuron (Cambridge Mass ) 68(5):991-1001 (2010)
  Attention or variations in event processing help drive learning. Lesion studies have implicated the central nucleus of the amygdala (CeA) in this process, particularly when expected rewards are omitted. However, lesion studies cannot specify how information processing in CeA supports such learning. To address these questions, we recorded CeA neurons in rats performing a task in which rewards were delivered or omitted unexpectedly. We found that activity in CeA neurons increased selectively at the time of omission and declined again with learning. Increased firing correlated with CeA-inactivation sensitive measures of attention. Notably CeA neurons did not fire to the cues or in response to unexpected rewards. These results indicate that CeA contributes to learning in response to reward omission due to a specific role in signaling actual omission rather than a more general involvement in signaling expectancies, errors, or reward value.
• A Motion Direction Map in Macaque V2
  - Neuron (Cambridge Mass ) 68(5):1002-1013 (2010)
  In mammals, the perception of motion starts with direction-selective neurons in the visual cortex. Despite numerous studies in monkey primary and second visual cortex (V1 and V2), there has been no evidence of direction maps in these areas. In the present study, we used optical imaging methods to study the organization of motion response in macaque V1 and V2. In contrast to the findings in other mammals (e.g., cats and ferrets), we found no direction maps in macaque V1. Robust direction maps, however, were found in V2 thick/pale stripes and avoided thin stripes. In many cases direction maps were located within thick stripes and exhibited pinwheel or linear organizations. The presence of motion maps in V2 points to a newfound prominence of V2 in motion processing, for contributing to motion perception in the dorsal pathway and/or for motion cue-dependent form perception in the ventral pathway. 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 (8513 K)
• The ACAT Inhibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model of Alzheimer's Disease
  - Neuron (Cambridge Mass ) 68(5):1014 (2010)