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This Week in The JournalF Cellular/Molecular

Snapin-Less Mice and ChromaffinCell ExocytosisJin-Hua Tian, Zheng-Xing Wu, MichaelUnzicker, Li Lu, Qian Cai, Cuiling Li,Claudia Schirra, Ulf Matti, DavidStevens, Chuxia Deng, Jens Rettig, andZu-Hang Sheng

(see pages 10546 –10555)

The calcium-dependent exocytosis of syn-aptic vesicles requires assembly of the sol-uble N-ethyl maleimide sensitive factoradaptor protein receptor (SNARE) com-plex, consisting of the vesicular mem-brane-associated protein synaptobrevin,the plasma membrane-associated proteinsyntaxin, and synaptosomal-associatedprotein 25 kDa (SNAP-25). Before re-lease, the calcium-sensing protein synap-totagmin also must bind SNAP-25.Snapin, first identified as a SNAP-25-binding protein, enhances the associationof synaptotagmin with SNAP-25. Thisweek, Tian et al. examine the role ofsnapin in the release of dense-core vesiclesin chromaffin cells using snapin-deficientmice. Heterozygous animals appearednormal, but homozygotes did not survivepast birth. Although the loss of snapin didnot affect formation of the SNARE com-plex, it did reduce the association betweenSNAP-25 and synaptotagmin. In chro-maffin cells lacking snapin, the fast exocy-totic burst of release was reduced bynearly one-half and was rescued by over-expression of snapin. Snapin appears tostabilize the readily releasable pool ofprimed vesicles.

Œ Development/Plasticity/Repair

Two Axon Branches, Two Targets,Two Guidance MoleculesYan Liu and Mary C. Halloran

(see pages 10556 –10563)

Axons and dendrites often respond differ-entially to guidance factors in developingtheir characteristic patterns and orienta-tions, but what about cells that send two

axons along distinct paths? This week, Liuand Halloran address that question inRohon-Beard (RB) sensory neurons in ze-brafish embryos. Using live imaging, theauthors report that central axons chuggedalong straight paths at a steady 20 �m/h.Peripheral axons emerged from the cen-tral axon and exited the spinal cord, scat-tering and branching often to form an epi-dermal network covering the trunk. Theauthors injected antisense morpholinos toknock down, or cDNAs to misexpress,putative guidance molecules. Sema-phorin3D, normally expressed in the spi-nal cord roof plate, repelled peripheral butnot central axons, suggesting it may guideperipheral axons out of the spinal cord.The RB-expressed Ig superfamily mole-cule transient axonal glycoprotein-1,however, was required for forward growthof central axons but had no effect on pe-ripheral axons.

f Behavioral/Systems/Cognitive

The Rubber-Hand Illusion RevisitedH. Henrik Ehrsson, Nicholas P. Holmes,and Richard E. Passingham

(see pages 10564 –10572)

In this week’s Journal, Ehrsson et al. testedthe feeling of body ownership using thesomewhat creepy sensation associatedwith the rubber-hand illusion. In the au-thors’ version of the illusion, blindfoldedparticipants were guided to touch a rub-ber hand with their left index finger. Si-multaneously, the experimenter touchedsubjects on their right hand, creating, af-ter some seconds, the feeling in most sub-jects that they were touching their ownhand. The rubber hand, experimenter,and subjects all wore gloves to minimizetactile differences. Temporal synchrony ofthe sensory signals was key to the illusion.As opposed to previous uses of the illu-sion, these experiments did not include avisual component, showing that tactileand proprioceptive sensations are suffi-cient to fool the subject into ownership ofthe hand. Functional magnetic resonanceimaging revealed that the ventral premo-tor and intraparietal cortices and cerebel-lum were activated during the illusion to a

degree that correlated with the strength ofthe illusion.

� Neurobiology of Disease

A2A, mGlu5, and ParkinsonismAnil Kachroo, Lianna R. Orlando, DavidK. Grandy, Jiang-Fan Chen, Anne B.Young, and Michael A. Schwarzschild

(see pages 10414 –10419)

Antagonists for the metabotropic gluta-mate receptor mGlu5 and the adenosinereceptor A2A have shown anti-parkin-sonian effects in preclinical studies. Thesereceptors also assemble in heteromericcomplexes in the striatum, suggestingthey might work in concert. This week,Kachroo et al. treated mice with reserpine,which depletes striatal dopamine, and ex-amined interactions between mGlu5 andA2A receptors. In normal and dopamine-depleted mice, the mGlu5 antagonist2-methyl-6-(phenylethynyl)-pyridine(MPEP) induced locomotor activity thatwas augmented by the A2A antagonistKW-6002. The MPEP action was absent inmice lacking mGlu5 receptors and, inter-estingly, also in mice lacking A2A recep-tors, D2 dopamine receptors, or both. Thebehavior was similarly missing from micein which A2A receptors were conditionallyknocked out in postnatal forebrain, thusexcluding a developmental effect. The D1

dopamine receptor agonist SKF 38393,however, increased motor behavior in allgenotypes.

Want to test your sense of body ownership? Try the somaticrubber hand illusion. See the article by Ehrsson et al. fordetails.

The Journal of Neuroscience, November 9, 2005 • 25(45):i • i

Cover picture: A computer-rendered right-hemisphere looking at a slant rivalry stimulus. The

image is rendered such that when viewed withanaglyphic filters (i.e., a red filter in front of the left

eye and a green filter in front of the right eye),stereoscopic depth is perceived. See article by

Brouwer et al. for details (pages 10403–10413). Thiscover image may also be viewed in 3-D at

www.jneurosci.org/content/vol25/issue45 withanaglyphic glasses. For a set of anaglyphic glasses,

print subscribers may send a self-addressed, stampedenvelope to the Journal Central Office. Anaglyphic

glasses available while supplies last.

i This Week in The Journal

Journal Club

10337 Not Every Graft Has What It Takes to Attract a Mossy FiberYevgenia Kozorovitskiy

10339 The Tuning Properties of Antennal Lobe Projection NeuronsJason Aungst and Marc Spehr

Toolbox

10341 Brain Microarray: Finding Needles in Molecular HaystacksNicole M. Lewandowski and Scott A. Small

Symposia and Mini-Symposia

10347 Neural Circuitry Underlying Rule Use in Humans and Nonhuman PrimatesSilvia A. Bunge, Jonathan D. Wallis, Amanda Parker, Marcel Brass,Eveline A. Crone, Eiji Hoshi, and Katsuyuki Sakai

10351 Lateralization of the Vertebrate Brain: Taking the Side of Model SystemsMarnie E. Halpern, Onur Gunturkun, William D. Hopkins, and Lesley J. Rogers

10358 Flashy Science: Controlling Neural Function with LightScott M. Thompson, Joseph P. Y. Kao, Richard H. Kramer, Kira E. Poskanzer,R. Angus Silver, David Digregorio, and Samuel S.-H. Wang

10366 New Neurons in the Adult Mammalian Brain: Synaptogenesis and FunctionalIntegrationHongjun Song, Gerd Kempermann, Linda Overstreet Wadiche, Chunmei Zhao,Alejandro F. Schinder, and Josef Bischofberger

10369 Time and the Brain: How Subjective Time Relates to Neural TimeDavid M. Eagleman, Peter U. Tse, Dean Buonomano, Peter Janssen,Anna Christina Nobre, and Alex O. Holcombe

10372 The Role of RNA and RNA Processing in NeurodegenerationJean-Marc Gallo, Peng Jin, Charles A. Thornton, Hong Lin, Janice Robertson,Ian D’Souza, and William W. Schlaepfer

10376 Wnt Signaling in Neural Circuit DevelopmentLee G. Fradkin, Gian Garriga, Patricia C. Salinas, John B. Thomas, Xiang Yu, andYimin Zou

10379 Epigenetic Mechanisms and Gene Networks in the Nervous SystemChristine M. Colvis, Jonathan D. Pollock, Richard H. Goodman, Soren Impey,John Dunn, Gail Mandel, Frances A. Champagne, Mark Mayford, Edward Korzus,Arvind Kumar, William Renthal, David E. H. Theobald, and Eric J. Nestler

The Journal of NeuroscienceNovember 9, 2005 • Volume 25 Number 45 www.jneurosci.org

10390 Neurobiological Mechanisms of the Placebo EffectFabrizio Benedetti, Helen S. Mayberg, Tor D. Wager, Christian S. Stohler, andJon-Kar Zubieta

ArticlesCELLULAR/MOLECULAR

10462 Kinetics and Spontaneous Open Probability Conferred by the � Subunit of the GABAA

ReceptorDavid A. Wagner, Marcel P. Goldschen-Ohm, Tim G. Hales, and Mathew V. Jones

10469 Gephyrin Regulates the Cell Surface Dynamics of Synaptic GABAA ReceptorsTija C. Jacob, Yury D. Bogdanov, Christopher Magnus, Richard S. Saliba,Josef T. Kittler, Philip G. Haydon, and Stephen J. Moss

10479 Src-Family Kinases Stabilize the Neuromuscular Synapse In Vivo via ProteinInteractions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine ReceptorsGayathri Sadasivam, Raffaella Willmann, Shuo Lin, Susanne Erb-Vogtli,Xian Chu Kong, Markus A. Ruegg, and Christian Fuhrer

10520 Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets ofGABAergic Neurons in the HippocampusFrancesco Ferraguti, Thomas Klausberger, Philip Cobden, Agnes Baude,J. David B. Roberts, Peter Szucs, Ayae Kinoshita, Ryuichi Shigemoto,Peter Somogyi, and Yannis Dalezios

10537 Dopamine Modulation of State-Dependent Endocannabinoid Release and Long-TermDepression in the StriatumAnatol C. Kreitzer and Robert C. Malenka

� 10546 The Role of Snapin in Neurosecretion: Snapin Knock-Out Mice Exhibit ImpairedCalcium-Dependent Exocytosis of Large Dense-Core Vesicles in Chromaffin CellsJin-Hua Tian, Zheng-Xing Wu, Michael Unzicker, Li Lu, Qian Cai, Cuiling Li,Claudia Schirra, Ulf Matti, David Stevens, Chuxia Deng, Jens Rettig, andZu-Hang Sheng

DEVELOPMENT/PLASTICITY/REPAIR

10437 Migration from a Mitogenic Niche Promotes Cell-Cycle ExitYoojin Choi, Paul R. Borghesani, Jennifer A. Chan, and Rosalind A. Segal

Œ 10556 Central and Peripheral Axon Branches from One Neuron Are Guided Differentially bySemaphorin3D and Transient Axonal Glycoprotein-1Yan Liu and Mary C. Halloran

BEHAVIORAL/SYSTEMS/COGNITIVE

10403 Activation in Visual Cortex Correlates with the Awareness of Stereoscopic DepthGijs Joost Brouwer, Raymond van Ee, and Jens Schwarzbach

10420 Neural Activity in Macaque Parietal Cortex Reflects Temporal Integration of VisualMotion Signals during Perceptual Decision MakingAlexander C. Huk and Michael N. Shadlen

10446 Localization and Identification of Concurrent Sounds in the Owl’s Auditory SpaceMapClifford H. Keller and Terry T. Takahashi

10494 Event-Related Brain Potential Correlates of Human Auditory Sensory Memory-TraceFormationCorinna Haenschel, David J. Vernon, Prabuddh Dwivedi, John H. Gruzelier, andTorsten Baldeweg

10510 Peptide YY3–36 Inhibits Both Anorexigenic Proopiomelanocortin and OrexigenicNeuropeptide Y Neurons: Implications for Hypothalamic Regulation of EnergyHomeostasisClaudio Acuna-Goycolea and Anthony N. van den Pol

f 10564 Touching a Rubber Hand: Feeling of Body Ownership Is Associated with Activity inMultisensory Brain AreasH. Henrik Ehrsson, Nicholas P. Holmes, and Richard E. Passingham

NEUROBIOLOGY OF DISEASE

� 10414 Interactions between Metabotropic Glutamate 5 and Adenosine A2A Receptors inNormal and Parkinsonian MiceAnil Kachroo, Lianna R. Orlando, David K. Grandy, Jiang-Fan Chen,Anne B. Young, and Michael A. Schwarzschild

10502 Silencing Primary Dystonia: Lentiviral-Mediated RNA Interference Therapy for DYT1DystoniaPedro Gonzalez-Alegre, Nicole Bode, Beverly L. Davidson, and Henry L. Paulson

10573 Errata: In the article “Differential Maturation of GABA Action and Anion Reversal Potentialin Spinal Lamina I Neurons: Impact of Chloride Extrusion Capacity,” by Matilde Cordero-Erausquin, Jeffrey A. M. Coull, Dominic Boudreau, Matthias Rolland, and Yves De Koninck,which appeared on pages 9613–9623 of the October 19, 2005 issue, the most recent versionsof Figures 6 and 7 were not used because of a printer’s error. The correct versions of bothfigures, as well as each corresponding legend, are printed in this issue.

10575 In the article “A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Lamininfrom Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischema” byZezong Gu, Jiankun Cui, Stephen Brown, Rafael Fridman, Shahriar Mobashery, Alex Y.Strongin, and Stuart A. Lipton, which appeared on pages 6401– 6408 of the July 6, 2005issue, the blots in Figure 2C contained a misprint. The labes for “Control” and “Ischemia”were inadvertently switched. This error was not reflected in the figure legend or thestatistical analysis in Figure 2D, and thus the conclusions of the study were not affected. Tomitigate this error, the authors have provided a corrected version of Figure 2 in this issue.

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JOURNAL CLUB

Not Every Graft Has What It Takes to Attract a Mossy Fiber

Yevgenia KozorovitskiyDepartment of Psychology and Program in Neuroscience, Princeton University, Princeton, New Jersey 08544

The Journal of Neuroscience, November 9, 2005 • 25(45):10337–10338

The Tuning Properties of Antennal Lobe Projection Neurons

Jason Aungst and Marc SpehrDepartment of Anatomy and Neurobiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201

The Journal of Neuroscience, November 9, 2005 • 25(45):10339 –10340

TOOLBOX

Brain Microarray: Finding Needles in Molecular Haystacks

Nicole M. Lewandowski and Scott A. SmallThe Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Neurology, and Center for Neurobiology and Behavior,

Columbia University College of Physicians and Surgeons, New York, New York 10032


MINI-SYMPOSIUM

Neural Circuitry Underlying Rule Use in Humans and Nonhuman Primates

Silvia A. Bunge,1 Jonathan D. Wallis,2 Amanda Parker,3 Marcel Brass,4 Eveline A. Crone,1,5 Eiji Hoshi,6 andKatsuyuki Sakai7

1Department of Psychology and Center for Mind and Brain, University of California at Davis, Davis, California 95616, 2Helen Wills Neuroscience Institute

and Department of Psychology, University of California at Berkeley, Berkeley, California 94720, 3Psychology, Brain, and Behaviour, University of Newcastle,

Newcastle upon Tyne NE1 7RU, United Kingdom, 4Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, D-04103

Leipzig, Germany, 5Department of Psychology, Leiden University, 2300 RA Leiden, The Netherlands, 6Brain Science Research Center, Tamagawa University

Research Institute, Machida, Tokyo 194-8610, Japan, and 7Graduate School of Medicine, University of Tokyo, Hongo Bunkyo-ku, Tokyo 113-8654, Japan


SYMPOSIUM

Lateralization of the Vertebrate Brain: Taking the Side of Model Systems

Marnie E. Halpern,1* Onur Gunturkun,2* William D. Hopkins,3,4 and Lesley J. Rogers5

1Carnegie Institution of Washington, Department of Embryology, Baltimore, Maryland 21218, 2Department of Biopsychology, Institute for Cognitive

Neuroscience, Faculty of Psychology, Ruhr-Universitat Bochum, 44780 Bochum, Germany, 3Berry College, Mount Berry, Georgia 30149, 4Division of

Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322, and 5Centre for Neuroscience and Animal Behaviour,

University of New England, School of Biological, Biomedical, and Molecular Sciences, Armidale, New South Wales 2351, Australia


http://www.jneurosci.org/cgi/content/full/25/45/10337





MINI-SYMPOSIUM

Flashy Science: Controlling Neural Function with Light

Scott M. Thompson,1 Joseph P. Y. Kao,1,2 Richard H. Kramer,3 Kira E. Poskanzer,4 R. Angus Silver,5 David Digregorio,5

and Samuel S.-H. Wang6

1Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, 2Medical Biotechnology Center, University of

Maryland Biotechnology Institute, Baltimore, Maryland 21201, 3Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley,

California 94720, 4Department of Biochemistry, University of California, San Francisco, San Francisco, California 94143, 5Department of Physiology,

University College, London WC1E 6BT, United Kingdom, and 6Department of Molecular Biology and Program in Neuroscience, Princeton University,

Princeton, New Jersey 08544


New Neurons in the Adult Mammalian Brain: Synaptogenesis and Functional Integration

Hongjun Song,1 Gerd Kempermann,2 Linda Overstreet Wadiche,3 Chunmei Zhao,4 Alejandro F. Schinder,5 andJosef Bischofberger6

1Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,2Max Delbruck Center for Molecular Medicine Berlin-Buch, 13125 Berlin, Germany, 3Vollum Institute, Oregon Health and Sciences University, Portland,

Oregon 97239, 4Laboratory of Genetics, The Salk Institute, La Jolla, California 92037, 5Laboratory of Neuronal Plasticity, Leloir Institute, 1405 Buenos Aires,

Argentina, and 6Physiology Department, University of Freiburg, D-79104 Freiburg, Germany


Time and the Brain: How Subjective Time Relates to Neural Time

David M. Eagleman,1 Peter U. Tse,2 Dean Buonomano,3 Peter Janssen,4 Anna Christina Nobre,5 and Alex O. Holcombe6

1Neurobiology and Anatomy, University of Texas–Houston, Houston, Texas 77030, 2Physiological and Brain Sciences, Dartmouth College, Hanover, New

Hampshire 03755, 3Department of Neurobiology, University of California, Los Angeles Brain Research Institute, Los Angeles, California 90095,4Laboratorium voor Neuro-en Psychofysiologie, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, 5Department of Experimental Psychology,

University of Oxford, Oxford OX1 2JD, United Kingdom, and 6School of Psychology, Cardiff University, CF10 3XQ Wales, United Kingdom

Most of the actions our brains perform on a daily basis, such as perceiving, speaking, and driving a car, require timing on the scale of tens to hundreds of milliseconds. Newdiscoveries in psychophysics, electrophysiology, imaging, and computational modeling are contributing to an emerging picture of how the brain processes, learns, andperceives time.The Journal of Neuroscience, November 9, 2005 • 25(45):10369 –10371

The Role of RNA and RNA Processing in Neurodegeneration

Jean-Marc Gallo,1 Peng Jin,2 Charles A. Thornton,3 Hong Lin,4 Janice Robertson,5 Ian D’Souza,6 andWilliam W. Schlaepfer4

1Medical Research Council Centre for Neurodegeneration Research and Department of Neurology, Institute of Psychiatry, King’s College London, London

SE5 8AF, United Kingdom, 2Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, 3Department of Neurology,

University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, 4Division of Neuropathology, University of Pennsylvania Medical

School, Philadelphia, Pennsylvania 19104-6100, 5University of Toronto, Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada M5S

3H2, and 6University of Washington and Veterans Affairs Medical Center, Seattle, Washington 98108






Wnt Signaling in Neural Circuit Development

Lee G. Fradkin,1 Gian Garriga,2 Patricia C. Salinas,3 John B. Thomas,4 Xiang Yu,5 and Yimin Zou6

1Department of Molecular and Cell Biology, Leiden University Medical Center, 2333 AL, Leiden, The Netherlands, 2Department of Molecular and CellBiology, University of California, Berkeley, Berkeley, California 94720, 3Department of Anatomy and Developmental Biology, University College London,London WC1E 6BT, United Kingdom, 4Salk Institute, San Diego, California 92186, 5Institute of Neuroscience, Chinese Academy of Sciences, Shanghai200031, China, and 6Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637The Journal of Neuroscience, November 9, 2005 • 25(45):10376 –10378

SYMPOSIUM

Epigenetic Mechanisms and Gene Networks in the Nervous System

Christine M. Colvis,1 Jonathan D. Pollock,1 Richard H. Goodman,2 Soren Impey,2 John Dunn,3 Gail Mandel,4

Frances A. Champagne,5 Mark Mayford,6 Edward Korzus,6 Arvind Kumar,7 William Renthal,7 David E. H. Theobald,7

and Eric J. Nestler7

1Genetics and Molecular Neurobiology Research Branch, Division of Basic Neurosciences and Behavioral Research, National Institute on Drug Abuse,Bethesda, Maryland 20892, 2Oregon Health and Science University, Vollum Institute, Portland, Oregon 97201-3098, 3Biology Department, BrookhavenNational Laboratory, Upton, New York 11973-5000, 4Howard Hughes Medical Institute, Department of Neurobiology and Behavior, State University of NewYork, Stony Brook, New York 11794-5230, 5Subdepartment of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB3 8AA, UnitedKingdom, 6Institute for Childhood and Neglected Disease, Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037-1000, and7Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070The Journal of Neuroscience, November 9, 2005 • 25(45):10379 –10389

Neurobiological Mechanisms of the Placebo Effect

Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5

1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, EmoryUniversity, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University ofMaryland, Baltimore, Maryland 21201, and 5Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, The University of Michigan,Ann Arbor, Michigan 48109The Journal of Neuroscience, November 9, 2005 • 25(45):10390 –10402

Articles

CELLULAR/MOLECULAR

Kinetics and Spontaneous Open Probability Conferred by the � Subunit of the GABAA Receptor

David A. Wagner,1 Marcel P. Goldschen-Ohm,2 Tim G. Hales,3 and Mathew V. Jones2

1Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53201, 2Department of Physiology, University of Wisconsin, Madison,

Wisconsin 53706, and 3Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care Medicine, The George Washington University,

Washington, DC 20037

GABAA receptors mediate synaptic and extrasynaptic inhibition. Native receptors consist of � and � subunits, which are required for function, and another “modulatory”subunit, for example, �, �, or �. Of these, the � subunit has the most restricted distribution, confers resistance to neurosteroid and anesthetic modulation, and causesspontaneous channel opening. Little is known, however, about how � affects receptor kinetics, which in turn shape responses to both ambient and synaptic GABA exposure.Here, we expressed human �2�1, �2�1�2, or �2�1� subunit combinations in human embryonic kidney 293 cells and used rapid solution exchange to study receptorkinetics in outside-out patches. The � subunit greatly slowed deactivation and recovery after brief GABA pulses. During long, saturating GABA pulses, the rate ofdesensitization was slower for �2�1� and �2�1�2 than for �2�1. However, in �2�1�, the final extent of desensitization was large compared with that of �2�1�2.Responses in �2�1�, but not the others, were often followed by an “overshoot” above the baseline, suggesting that a fraction of channels are spontaneously open and aretransiently silenced by receptor activation and subsequent desensitization. The baseline current and associated noise were reduced by picrotoxin, revealing that�-containing channels are open �4% of the time in the absence of GABA. These results suggest that, if �-containing receptors are expressed at synapses, the synaptic





currents would be long-lasting but may rundown quickly under high-frequency activation. In addition, silencing of spontaneous openings by desensitization raises thepossibility that tonic inhibition mediated by �-containing receptors may be regulated by phasic inhibition.The Journal of Neuroscience, November 9, 2005 • 25(45):10462–10468

Gephyrin Regulates the Cell Surface Dynamics of Synaptic GABAA Receptors

Tija C. Jacob,1* Yury D. Bogdanov,2* Christopher Magnus,2 Richard S. Saliba,2 Josef T. Kittler,1 Philip G. Haydon,1 andStephen J. Moss1,2

1Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and 2Department of Neuroscience, University of

Pennsylvania, Philadelphia, Pennsylvania 19104

The efficacy of fast synaptic inhibition is critically dependent on the accumulation of GABAA receptors at inhibitory synapses, a process that remains poorly understood.Here, we examined the dynamics of cell surface GABAA receptors using receptor subunits modified with N-terminal extracellular ecliptic pHluorin reporters. In hippocam-pal neurons, GABAA receptors incorporating pHluorin-tagged subunits were found to be clustered at synaptic sites and also expressed as diffuse extrasynaptic staining. Bycombining FRAP (fluorescence recovery after photobleaching) measurements with live imaging of FM4-64-labeled active presynaptic terminals, it was evident thatclustered synaptic receptors exhibit significantly lower rates of mobility at the cell surface compared with their extrasynaptic counterparts. To examine the basis of thisconfinement, we used RNAi to inhibit the expression of gephyrin, a protein shown to regulate the accumulation of GABAA receptors at synaptic sites. However, whethergephyrin acts to control the actual formation of receptor clusters, their stability, or is simply a global regulator of receptor cell surface number remains unknown. Inhibitinggephyrin expression did not modify the total number of GABAA receptors expressed on the neuronal cell surface but significantly decreased the number of receptor clusters.Live imaging revealed that clusters that formed in the absence of gephyrin were significantly more mobile compared with those in control neurons. Together, our resultsdemonstrate that synaptic GABAA receptors have lower levels of lateral mobility compared with their extrasynaptic counterparts, and suggest a specific role for gephyrinin reducing the diffusion of GABAA receptors, facilitating their accumulation at inhibitory synapses.The Journal of Neuroscience, November 9, 2005 • 25(45):10469 –10478

Src-Family Kinases Stabilize the Neuromuscular Synapse In Vivo via Protein Interactions,Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors

Gayathri Sadasivam,1 Raffaella Willmann,1 Shuo Lin,2 Susanne Erb-Vogtli,1 Xian Chu Kong,2 Markus A. Ruegg,2 andChristian Fuhrer1

1Department of Neurochemistry, Brain Research Institute, University of Zurich, CH-8057 Zurich, Switzerland, and 2Biozentrum, University of Basel, CH-

4056 Basel, Switzerland

Postnatal stabilization and maturation of the postsynaptic membrane are important for development and function of the neuromuscular junction (NMJ), but the under-lying mechanisms remain poorly characterized. We examined the role of Src-family kinases (SFKs) in vivo. Electroporation of kinase-inactive Src constructs into soleusmuscles of adult mice caused NMJ disassembly: acetylcholine receptor (AChR)-rich areas became fragmented; the topology of nerve terminal, AChRs, and synaptic nucleiwas disturbed; and occasionally nerves started to sprout. Electroporation of kinase-overactive Src produced similar but milder effects. We studied the mechanism of SFKaction using cultured src�/�;fyn�/� myotubes, focusing on clustering of postsynaptic proteins, their interaction with AChRs, and AChR phosphorylation. Rapsyn and theutrophin-glycoprotein complex were recruited normally into AChR-containing clusters by agrin in src�/�;fyn�/� myotubes. But after agrin withdrawal, clusters of theseproteins disappeared rapidly in parallel with AChRs, revealing that SFKs are of general importance in postsynaptic stability. At the same time, AChR interaction with rapsynand dystrobrevin and AChR phosphorylation decreased after agrin withdrawal from mutant myotubes. Unexpectedly, levels of rapsyn protein were increased in src�/�;fyn�/� myotubes, whereas rapsyn– cytoskeleton interactions were unaffected. The overall cytoskeletal link of AChRs was weak but still strengthened by agrin in mutantcells, consistent with the normal formation but decreased stability of AChR clusters. These data show that correctly balanced activity of SFKs is critical in maintaining adultNMJs in vivo. SFKs hold the postsynaptic apparatus together through stabilization of AChR–rapsyn interaction and AChR phosphorylation. In addition, SFKs controlrapsyn levels and AChR-cytoskeletal linkage.The Journal of Neuroscience, November 9, 2005 • 25(45):10479 –10493




Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergicNeurons in the Hippocampus

Francesco Ferraguti,1,2 Thomas Klausberger,1,3 Philip Cobden,1 Agnes Baude,1,4 J. David B. Roberts,1 Peter Szucs,5

Ayae Kinoshita,6 Ryuichi Shigemoto,7 Peter Somogyi,1 and Yannis Dalezios1,8

1Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, Oxford University, Oxford OX1 3TH, United Kingdom,2Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria, 3Centre for Brain Research, Medical University Vienna, A-1090Vienna, Austria, 4Laboratoire de NeuroPhysiologie Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6150, 13402 Cedex 20Marseille, France, 5Department of Anatomy, Histology, and Embryology, Faculty of Medicine, Medical and Health Centre, University of Debrecen, H-4012Debrecen, Hungary, 6Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan, 7Division ofCerebral Structure, National Institute for Physiological Sciences, Okazaki 444-8787, Japan, and 8Department of Basic Sciences, Faculty of Medicine,University of Crete, GR-71003 Heraklion, Greece

Presynaptic metabotropic glutamate receptors (mGluRs) show a highly selective expression and subcellular location in nerve terminals modulating neurotransmitterrelease. We have demonstrated that alternatively spliced variants of mGluR8, mGluR8a and mGluR8b, have an overlapping distribution in the hippocampus, and besidesperforant path terminals, they are expressed in the presynaptic active zone of boutons making synapses selectively with several types of GABAergic interneurons, primarilyin the stratum oriens. Boutons labeled for mGluR8 formed either type I or type II synapses, and the latter were GABAergic. Some mGluR8-positive boutons also expressedmGluR7 or vasoactive intestinal polypeptide. Interneurons strongly immunopositive for the muscarinic M2 or the mGlu1 receptors were the primary targets of mGluR8-containing terminals in the stratum oriens, but only neurochemically distinct subsets were innervated by mGluR8-enriched terminals. The majority of M2-positive neuronswere mGluR8 innervated, but a minority, which expresses somatostatin, was not. Rare neurons coexpressing calretinin and M2 were consistently targeted by mGluR8-positive boutons. In vivo recording and labeling of an mGluR8-decorated and strongly M2-positive interneuron revealed a trilaminar cell with complex spike bursts duringtheta oscillations and strong discharge during sharp wave/ripple events. The trilaminar cell had a large projection from the CA1 area to the subiculum and a preferentialinnervation of interneurons in the CA1 area in addition to pyramidal cell somata and dendrites. The postsynaptic interneuron type-specific expression of the high-efficacypresynaptic mGluR8 in both putative glutamatergic and in identified GABAergic terminals predicts a role in adjusting the activity of interneurons depending on the levelof network activity.The Journal of Neuroscience, November 9, 2005 • 25(45):10520 –10536

Dopamine Modulation of State-Dependent Endocannabinoid Release and Long-TermDepression in the Striatum

Anatol C. Kreitzer and Robert C. MalenkaDepartment of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University Medical School, Palo Alto, California 94305

Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensivelyoutside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, abrain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yielddetectable endocannabinoid release. However, when paired with postsynaptic depolarization sufficient to activate L-type calcium channels, activation of postsynapticmetabotropic glutamate receptors (mGluRs), either by high-frequency tetanic stimulation or an agonist, induced eCB-LTD. Pairing bursts of afferent stimulation with briefsubthreshold membrane depolarizations that mimicked down-state to up-state transitions also induced eCB-LTD, which not only required activation of mGluRs and L-typecalcium channels but also was bidirectionally modulated by dopamine D2 receptors. Consistent with network models, these results demonstrate that dopamine regulatesthe induction of a Hebbian form of long-term synaptic plasticity in the striatum. However, this gating of plasticity by dopamine is accomplished via an unexpectedmechanism involving the regulation of mGluR-dependent endocannabinoid release.The Journal of Neuroscience, November 9, 2005 • 25(45):10537–10545

The Role of Snapin in Neurosecretion: Snapin Knock-Out Mice Exhibit Impaired Calcium-Dependent Exocytosis of Large Dense-Core Vesicles in Chromaffin Cells

Jin-Hua Tian,1* Zheng-Xing Wu,2* Michael Unzicker,2 Li Lu,1 Qian Cai,1 Cuiling Li,3 Claudia Schirra,2 Ulf Matti,2

David Stevens,2 Chuxia Deng,3 Jens Rettig,2 and Zu-Hang Sheng1

1Synaptic Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701,2Physiologisches Institut, Universitaet des Saarlandes, 66424 Homburg/Saar, Germany, and 3Mammalian Genetics Section, Genetics of Development andDisease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Identification of the molecules that regulate the priming of synaptic vesicles for fusion and the structural coupling of the calcium sensor with the soluble N-ethyl maleimidesensitive factor adaptor protein receptor (SNARE)-based fusion machinery is critical for understanding the mechanisms underlying calcium-dependent neurosecretion.Snapin binds to synaptosomal-associated protein 25 kDa (SNAP-25) and enhances the association of the SNARE complex with synaptotagmin. In the present study, weabolished snapin expression in mice and functionally evaluated the role of Snapin in neuroexocytosis. We found that the association of synaptotagmin-1 with SNAP-25 inbrain homogenates of snapin mutant mice is impaired. Consequently, the absence of Snapin in embryonic chromaffin cells leads to a significant reduction of calcium-dependent exocytosis resulting from a decreased number of vesicles in releasable pools. Overexpression of Snapin fully rescued this inhibitory effect in the mutant cells.







Furthermore, Snapin is relatively enriched in the purified large dense-core vesicles of chromaffin cells and associated with synaptotagmin-1. Thus, our biochemical andelectrophysiological studies using snapin knock-out mice demonstrate that Snapin plays a critical role in modulating neurosecretion by stabilizing the release-readyvesicles.The Journal of Neuroscience, November 9, 2005 • 25(45):10546 –10555

DEVELOPMENT/PLASTICITY/REPAIR

Migration from a Mitogenic Niche Promotes Cell-Cycle Exit

Yoojin Choi,1,2 Paul R. Borghesani,1,2 Jennifer A. Chan,1,3 and Rosalind A. Segal1,2

1Department of Pediatric Oncology, Dana-Farber Cancer Institute, 2Department of Neurobiology, Harvard Medical School, and 3Department of Pathology,

Brigham and Women’s Hospital, Boston, Massachusetts 02115

During development, neural precursors proliferate in one location and migrate to the residence of their mature function. The transition from a proliferative stage to amigratory stage is a critical juncture; errors in this process may result in tumor formation, mental retardation, or epilepsy. This transition could be the result of a simplesequential process in which precursors exit the cell cycle and then begin to migrate or a dynamically regulated process in which migration away from a mitogenic nicheinduces precursors to exit the cell cycle. Here, we show, using in vivo and in vitro approaches, that granule cell precursors proliferate when they are exposed to themicroenvironment of the external granule cell layer (EGL) and exit the cell cycle as a result of migrating away from this environment. In vivo, granule cell precursors thatremain in the EGL because of impaired migration continue to proliferate in the mitogenic niche of the EGL. In vitro, granule cell precursors that are introduced into anorganotypic cerebellar slice proliferate preferentially in the EGL. We identify Sonic Hedgehog as a critical component of the EGL mitogenic niche. Together, these dataindicate that migration away from a mitogenic niche promotes transition from a proliferative to a nonproliferative, migratory stage.The Journal of Neuroscience, November 9, 2005 • 25(45):10437–10445

Central and Peripheral Axon Branches from One Neuron Are Guided Differentially bySemaphorin3D and Transient Axonal Glycoprotein-1

Yan Liu and Mary C. HalloranDepartments of Zoology and Anatomy, University of Wisconsin, Madison, Wisconsin 53706

For multiple axons from one neuron to extend in different directions to unique targets, the growth cones of each axon must have distinct responses to guidance cues.However, the mechanisms by which separate axon branches are guided along different pathways are mainly unknown. Zebrafish Rohon-Beard (R-B) sensory neuronsextend central axon branches in the spinal cord and peripheral axons to the epidermis. To investigate the differential guidance mechanisms of the central versus peripheralR-B axon branches, we used live-growth cone imaging in vivo combined with manipulation of individual guidance molecules. We show that a semaphorin expressed at thedorsal spinal cord midline, Semaphorin3D (Sema3D), may act to repel the peripheral axons out of the spinal cord. Sema3D knock-down reduces the number of peripheralaxons. Remarkably, Sema3D ectopic expression repels and induces branching of peripheral axons in vivo but has no effect on central axons from the same neurons.Conversely, central axons require a growth-promoting molecule, transient axonal glycoprotein-1 (TAG-1), to advance, whereas peripheral axons do not. After TAG-1knock-down, central growth cones display extensive protrusive activity but make little forward advance. TAG-1 knock-down has no effect on the motility or advance ofperipheral growth cones. These experiments show how Sema3D and TAG-1 regulate the motility and behavior of growth cones extending in their natural in vivo environ-ment and demonstrate that two different axon branches from one neuron respond differently to guidance cues in vivo.The Journal of Neuroscience, November 9, 2005 • 25(45):10556 –10563

BEHAVIORAL/SYSTEMS/COGNITIVE

Activation in Visual Cortex Correlates with the Awareness of Stereoscopic Depth

Gijs Joost Brouwer,1 Raymond van Ee,1 and Jens Schwarzbach2,3

1Helmholtz Institute, Utrecht University, 3584 CC Utrecht, The Netherlands, 2F. C. Donders Centre for Cognitive Neuroimaging, 6500 HB Nijmegen, The

Netherlands, and 3Maastricht University, 6200 MD Maastricht, The Netherlands

Using event-related functional magnetic resonance imaging, we studied the activation correlating with the awareness of stereoscopic depth using a bistable slanted surface(slant rivalry). Bistability resulted from incongruence between two slant-defining cues: binocular disparity and monocular perspective. The stimulus was perceived asalternating between the perspective-dominated percept (monocular depth) and the disparity-dominated percept (stereopsis), while sensory input remained constant,enabling us to study changes in awareness of depth associated with either cue. Transient activation relating to perceptual alternations was found bilaterally in the caudalpart of the intraparietal sulcus, in the right-hemispheric anterior intraparietal sulcus, within visual area V4d-topo, and inferior to area MT�. Transient activationcorrelating specifically with alternations toward the disparity-dominated percept was found in a number of visual areas, including dorsal visual areas V3A, V7, andV4d-topo and visual areas MT� and lateral occipital complex. No activation was found for alternations toward the perspective-dominated percept. Our results show thatof all visual areas responsive to disparity-defined depth, V4d-topo shows the most robust signal changes correlating with the instigation of stereoscopic depth awareness(stereopsis).The Journal of Neuroscience, November 9, 2005 • 25(45):10403–10413





Neural Activity in Macaque Parietal Cortex Reflects Temporal Integration of Visual MotionSignals during Perceptual Decision Making

Alexander C. Huk1 and Michael N. Shadlen2

1Section of Neurobiology, Center for Perceptual Systems, and Department of Psychology, University of Texas at Austin, Austin, Texas 78712, and 2Howard

Hughes Medical Institute, Department of Physiology and Biophysics and National Primate Research Center, University of Washington, Seattle, Washington

98195

Decision-making often requires the accumulation and maintenance of evidence over time. Although the neural signals underlying sensory processing have been studiedextensively, little is known about how the brain accrues and holds these sensory signals to guide later actions. Previous work has suggested that neural activity in the lateralintraparietal area (LIP) of the monkey brain reflects the formation of perceptual decisions in a random dot direction-discrimination task in which monkeys communicatetheir decisions with eye-movement responses. We tested the hypothesis that decision-related neural activity in LIP represents the time integral of the momentary motion“evidence.” By briefly perturbing the strength of the visual motion stimulus during the formation of perceptual decisions, we tested whether this LIP activity reflected apersistent, integrated “memory” of these brief sensory events. We found that the responses of LIP neurons reflected substantial temporal integration. Brief pulses hadpersistent effects on both the monkeys’ choices and the responses of neurons in LIP, lasting up to 800 ms after appearance. These results demonstrate that LIP is involvedin neural time integration underlying the accumulation of evidence in this task. Additional analyses suggest that decision-related LIP responses, as well as behavioralchoices and reaction times, can be explained by near-perfect time integration that stops when a criterion amount of evidence has been accumulated. Temporal integrationmay be a fundamental computation underlying higher cognitive functions that are dissociated from immediate sensory inputs or motor outputs.The Journal of Neuroscience, November 9, 2005 • 25(45):10420 –10436

Localization and Identification of Concurrent Sounds in the Owl’s Auditory Space Map

Clifford H. Keller and Terry T. TakahashiInstitute of Neuroscience, University of Oregon, Eugene, Oregon 97403

In nature, sounds from multiple sources sum at the eardrums, generating complex cues for sound localization and identification. In this clutter, the auditory system mustdetermine “what is where.” We examined this process in the auditory space map of the barn owl’s (Tyto alba) inferior colliculus using two spatially separated sourcessimultaneously emitting uncorrelated noise bursts, which were uniquely identified by different frequencies of sinusoidal amplitude modulation. Spatial response profilesof isolated neurons were constructed by testing the source-pair centered at various locations in virtual auditory space. The neurons responded whenever a source was placedwithin the receptive field, generating two clearly segregated foci of activity at appropriate loci. The spike trains were locked strongly to the amplitude modulation of thesource within the receptive field, whereas the other source had minimal influence. Two sources amplitude modulated at the same rate were resolved successfully, suggestingthat source separation is based on differences of fine structure. The spike rate and synchrony were stronger for whichever source had the stronger average binaural level.A computational model showed that neuronal activity was primarily proportional to the degree of matching between the momentary binaural cues and the preferred valuesof the neuron. The model showed that individual neurons respond to and synchronize with sources in their receptive field if there are frequencies having an averagebinaural-level advantage over a second source. Frequencies with interaural phase differences that are shared by both sources may also evoke activity, which may besynchronized with the amplitude modulations from either source.The Journal of Neuroscience, November 9, 2005 • 25(45):10446 –10461

Event-Related Brain Potential Correlates of Human Auditory Sensory Memory-Trace Formation

Corinna Haenschel,1,2 David J. Vernon,3 Prabuddh Dwivedi,4 John H. Gruzelier,4 and Torsten Baldeweg5

1Laboratory for Neurophysiology and Neuroimaging, Department of Psychiatry, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany, 2Max

Planck Institute for Brain Research, 60528 Frankfurt, Germany, 3Department of Applied Social Sciences, Canterbury Christ Church University College,

Canterbury CT1 1QU, United Kingdom, 4Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, London W6 8RP, United

Kingdom, and 5Institute of Child Health, University College London and Great Ormond Street Hospital for Children, London WC1N 1EH, United Kingdom

The event-related potential (ERP) component mismatch negativity (MMN) is a neural marker of human echoic memory. MMN is elicited by deviant sounds embedded ina stream of frequent standards, reflecting the deviation from an inferred memory trace of the standard stimulus. The strength of this memory trace is thought to beproportional to the number of repetitions of the standard tone, visible as the progressive enhancement of MMN with number of repetitions (MMN memory-trace effect).However, no direct ERP correlates of the formation of echoic memory traces are currently known. This study set out to investigate changes in ERPs to different numbers ofrepetitions of standards, delivered in a roving-stimulus paradigm in which the frequency of the standard stimulus changed randomly between stimulus trains. Normalhealthy volunteers (n � 40) were engaged in two experimental conditions: during passive listening and while actively discriminating changes in tone frequency. Aspredicted, MMN increased with increasing number of standards. However, this MMN memory-trace effect was caused mainly by enhancement with stimulus repetition ofa slow positive wave from 50 to 250 ms poststimulus in the standard ERP, which is termed here “repetition positivity” (RP). This RP was recorded from frontocentralelectrodes when participants were passively listening to or actively discriminating changes in tone frequency. RP may represent a human ERP correlate of rapid andstimulus-specific adaptation, a candidate neuronal mechanism underlying sensory memory formation in the auditory cortex.The Journal of Neuroscience, November 9, 2005 • 25(45):10494 –10501





Peptide YY3–36 Inhibits Both Anorexigenic Proopiomelanocortin and Orexigenic NeuropeptideY Neurons: Implications for Hypothalamic Regulation of Energy Homeostasis

Claudio Acuna-Goycolea and Anthony N. van den PolDepartment of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Peptide YY3–36 (PYY3–36) is released by endocrine cells of the gut and may serve as an important long-distance neuropeptide signal relating energy balance information tothe brain to depress food intake. The postulated mechanism is the activation of anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus.In striking contrast, using voltage and current-clamp recording, we found that PYY3–36 consistently, dose dependently, and reversibly inhibited POMC cells by reducingaction potentials, hyperpolarizing the membrane potential, decreasing input resistance and inward calcium currents, increasing G-protein-gated inwardly rectifying K �

channel currents, and presynaptically inhibiting release of excitatory glutamate. Importantly, we found PYY3–36 had similar inhibitory effects on identified orexigenicneuropeptide Y (NPY) neurons. In both cell types, these effects were blocked by BIIE0246, a Y2 receptor antagonist. Together, these data argue that anorexigenic actions ofPYY3–36 are mediated more likely by inhibition of NPY neurons. Dual PYY3–36 inhibition of both NPY and POMC cells may temporarily reduce the contribution of arcuatecells to feeding circuits, enhancing the role of other CNS loci.The Journal of Neuroscience, November 9, 2005 • 25(45):10510 –10519

Touching a Rubber Hand: Feeling of Body Ownership Is Associated with Activity inMultisensory Brain Areas

H. Henrik Ehrsson,1 Nicholas P. Holmes,2 and Richard E. Passingham1,2

1Wellcome Department of Cognitive Neurology, Institute of Neurology, London WC1N 3BG, United Kingdom, and 2Department of Experimental

Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom

In the “rubber-hand illusion,” the sight of brushing of a rubber hand at the same time as brushing of the person’s own hidden hand is sufficient to produce a feeling ofownership of the fake hand. We shown previously that this illusion is associated with activity in the multisensory areas, most notably the ventral premotor cortex (Ehrssonet al., 2004). However, it remains to be demonstrated that this illusion does not simply reflect the dominant role of vision and that the premotor activity does not reflect avisual representation of an object near the hand. To address these issues, we introduce a somatic rubber-hand illusion. The experimenter moved the blindfolded partici-pant’s left index finger so that it touched the fake hand, and simultaneously, he touched the participant’s real right hand, synchronizing the touches as perfectly as possible.After �9.7 s, this stimulation elicited an illusion that one was touching one’s own hand. We scanned brain activity during this illusion and two control conditions, usingfunctional magnetic resonance imaging. Activity in the ventral premotor cortices, intraparietal cortices, and the cerebellum was associated with the illusion of touchingone’s own hand. Furthermore, the rated strength of the illusion correlated with the degree of premotor and cerebellar activity. This finding suggests that the activity in theseareas reflects the detection of congruent multisensory signals from one’s own body, rather than of visual representations. We propose that this could be the mechanism forthe feeling of body ownership.The Journal of Neuroscience, November 9, 2005 • 25(45):10564 –10573

NEUROBIOLOGY OF DISEASE

Interactions between Metabotropic Glutamate 5 and Adenosine A2A Receptors in Normal andParkinsonian Mice

Anil Kachroo,1 Lianna R. Orlando,1 David K. Grandy,2 Jiang-Fan Chen,1 Anne B. Young,1 and Michael A. Schwarzschild1

1MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02129, and2Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201

Evidence for heteromeric receptor complexes comprising adenosine A2A and metabotropic glutamate 5 (mGlu5) receptors in striatum has raised the possibility ofsynergistic interactions between striatal A2A and mGlu5 receptors. We investigated the role of striatal A2A receptors in the locomotor stimulant and antiparkinsonianproperties of mGlu5 antagonists using complementary pharmacologic and genetic approaches. Locomotion acutely stimulated by the mGlu5 antagonist [2-methyl-6-(phenylethynyl)-pyridine (MPEP)] was absent in mGlu5 knock-out (KO) mice and was potentiated by an A2A antagonist KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine], both in normal and in dopamine-depleted (reserpinized) mice. Conversely, the MPEP-induced motor response was markedly attenuated in single anddouble A2A and D2 receptor KO mice. In contrast, motor stimulation by a D1 dopamine agonist was not attenuated in the KO mice. The A2A receptor dependence ofMPEP-induced motor stimulation was investigated further using a postnatal forebrain-specific conditional (Cre/loxP system) KO of the A2A receptor. MPEP loses the abilityto stimulate locomotion in conditional KO mice, suggesting that this mGlu5 antagonist effect requires the postdevelopmental action of striatal A2A receptors. Thepotentiation of mGlu5 antagonist-induced motor stimulation by an A2A antagonist and its dependence on both D2 and forebrain A2A receptors highlight the functionalinterdependence of these receptors. These data also strengthen a rationale for pursuing a combinational drug strategy for enhancing the antiparkinsonian effects of A2A andmGlu5 antagonists.The Journal of Neuroscience, November 9, 2005 • 25(45):10414 –10419







Silencing Primary Dystonia: Lentiviral-Mediated RNA Interference Therapy for DYT1 Dystonia

Pedro Gonzalez-Alegre,1 Nicole Bode,1 Beverly L. Davidson,1,2 and Henry L. Paulson1

Departments of 1Neurology and 2Medicine, Carver College of Medicine at the University of Iowa, Iowa City, Iowa 52242

DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by acommon three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying thedisease-linked mutation, torsinA(�E) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclearenvelope. Therefore, suppressing torsinA(�E) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentiallyeffective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(�E)and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immuno-deficiency virus effectively silenced torsinA(�E) in a neural model of the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstratingsignificant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These resultssupport the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease.The Journal of Neuroscience, November 9, 2005 • 25(45):10502–10509


Opportunities for research in US government laboratories in the fields of: Neurology Neurobiology Neurochemistry Neurophysiology Neuropsychology Neuropharmacology Neurotoxicology Neuroendocrinology and related disciplines

Among participating laboratories are: National Institutes of Health

US Army Research Laboratory US Naval Research Laboratory

US Air Force Research Laboratory US Army Night Vision Laboratory

FAA/Civil Aerospace Medical Institute US Environmental Protection Agency

Edgewood Chemical & Biological Center US Army Medical Research & Materiel Command

National Institute for Occupational Safety & Health Naval Medical Research Ctr/Naval Health Research Ctr

National Institutes of Health/National Institute of Standards and Technology, Joint Program

Competitive awards for independent research Duration of 12 months renewable for up to 3 years Annual stipend ranging from $38,000 to $65,000 for recent Ph.D. recipients; higher for additional experience Relocation, professional travel, health insurance Annual application deadlines Feb 1, May 1, Aug 1 and Nov 1

Detailed program information, including instructions on how to apply, can be obtained from the NRC Web site at:

www.national-academies.org/rap Questions should be directed to 202-334-2760 (tel) or [email protected]

Visit NRC booth # 3502 in the exhibit hall.

Qualified applicants will be reviewed without regard to race,

religion, color, age, sex or national origin.

Postdoctoral Research Awards Senior Research Awards

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Dystonia Medical Research Foundationwww.dystonia-foundation.org

2006 Funding OpportunitiesResearch Grants & Contracts–Grants & contracts are available in support of hypothesis-drivenresearch relative to the causes, mechanisms, prevention and treatment of the various forms of dysto-nia, the third most common neurologic movement disorder.Amount: $75,000/year up to 2 years; $100,000/year for 3 years (Fahn Award) for outstanding tenure-track junior faculty. Contracts are negotiable in duration and amount. Deadline: 1/10/06

Fellowships–This program is designed to assist post-doctoral fellows establish careers in researchrelevant to the field of dystonia. Amount: $50,000 per year for two years. Deadline: 1/10/06

Residency Elective Program–This program provides an opportunity for PGY 2 or 3 residentsin neurology to gain experience in the evaluation and treatment of patients with dystonia as“visiting trainees” with dystonia experts at their respective institutions. Amount: up to $4,000Deadline: on-going

Research materials, including brain tissue and reagents, are available to qualified investigators.For more information and applications, please contact DMRF

at 312.755.0198 or visit www.dystonia-foundation.org

Please visit us at SFN Booth #1113

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Endowed Chairs in Molecular NeuroscienceIndiana University seeks applications and nominations for three endowed professorships. These positions are part of the ongoing expansion of the Program in Neuroscience supported by a generous endowment, the construction of a new building to house the appointees, and the infusion of greater than $400 million since the year 2000 from state and private funds for life sciences research.

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The Linda and Jack Gill Centerfor Biomoleuclar Science

The area of focus for the positions is the genetic and molecular basis of synaptic plasticity broadly defined to include changes in synaptic activity as a result of experience, development or injury. The goal of these appointments is to attract internationally recognized scientists to enhance research and bring forth important discoveries in neuroscience.

Recently described by Newsweek as the “hottest big state school" in the United States, Indiana University is a vibrant and beautiful campus set amongst the hills of southern Indiana in Bloomington, a safe, culturally rich environment.

Nominations should include a letter describing the qualifications of the candidate along with contact information. Applications should include a statement of research interests, a curriculum vitae, and names of three references. The positions will remain open until filled, but for full consideration, please submit materials by January 15, 2006. Nominations and applications should be addressed to:

J. Michael WalkerIndiana University1101 E. 10th St.Bloomington, IN 47405 [email protected]

Indiana University is an Equal Opportunity/Affirmative Action Employer. Nominations of and applications from women and minorities are strongly encouraged.

MIDDLEBURY COLLEGE Tenure-track position in Biopsychology/Behavioral

Neuroscience The Department of Psychology invites applications for a tenure-track position in Biopsychology/Behavioral Neuroscience beginning September 2006. We are interested in a neuroscientist whose research focuses on nonhuman species. The successful candidate must be able to teach Biopsychology or Behavioral Neuroscience, Learning, Introduction to Psychology, and upper and mid-level courses in areas of biopsychology or neuroscience. Appointments will be made at the rank of Assistant Professor (Ph.D.) or Instructor (ABD). The psychology department at Middlebury College is committed to exceptional teaching and to the involvement of undergraduates in an active research program. The department is housed in a state-of-the-art science center and currently has eleven fully equipped faculty research labs. Candidates should provide evidence of commitment to excellent teaching and of their desire to develop and sustain a program of research, including research that actively involves undergraduates at a liberal arts institution. Please send a letter of application with a statement of teaching and research interests, copies of teaching evaluations, curriculum vitae, graduate transcript, a sample of scholarly work, and three current letters of recommendation, at least two of which must speak to teaching ability, to:

Professor Carlos Vélez, Chair; Department of Psychology;

Middlebury College; Middlebury, VT 05753. Review of applications will begin November 1, 2005 and continue until the position is filled. Middlebury College is an Equal Opportunity Employer committed to recruiting a diverse faculty to complement the increasing diversity of our student body.

RESEARCH GRANT AWARDS

Five-Year named Chairs for Senior and JuniorFaculty, maximum of $1,100,000 over a five-year period.One-Time Start-Up Cost Grant, maximum of$1,000,000. Individual Grants, maximum of $200,000per year, research grants for basic or clinical research onspinal cord injury and disease. Postdoctoral &Graduate Student Fellowship Awards. Applicantsmust be associated with a New Jersey Institution and maycollaborate with researchers out-of-state and country.

Application form and details at:www.state.nj.us/health/spinalcord/

Application form and details from:

New Jersey Commission on Spinal Cord ResearchPO Box 360; Market and Warren Streets

Trenton, New Jersey 08625-0360Tel: 609-292-4055. E-mail: [email protected]

Closing Date for Grant Applications: December 8, 2005

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Assistant/Associate Professor Behavioral Neuropharmacology

The Department of Pharmacology, University of Tennessee (UT) Health Science Center (website: http://www.utmem.edu/pharmacology), invites applications for a tenure-track assistant/associate professor faculty position in the area of behavioral pharmacology or behavioral neuroscience. We seek a faculty member who will be a major contributor to the UT Center of Excellence in the Neurobiology of Brain Diseases. The faculty member will direct an independent program in an aspect of psychopharmacology or drug abuse research. Ideal candidates will be those who employ an integrative, mechanistic approach, utilizing neurochemical, molecular or electrophysiological techniques to complement their behavioral research. Candidates who will administer a core animal behavior laboratory will receive additional consideration. Candidates should be enthusiastic about engaging in collaborative research within a highly interactive, well-funded community of neuroscientists. The selected candidate will participate in the teaching of graduate and professional students. Applicants should have a doctorate in pharmacology, neuroscience, experimental psychology or a related discipline, and relevant postdoctoral experience. Applications will be reviewed beginning December 1, 2005, but will continue to be accepted until the position is filled. Curriculum vitae, statement of research interests and three reference letters should be sent to:

Jeffery D. Steketee, Ph.D., Behavioral Neuropharmacology Search Committee Department of Pharmacology, University of Tennessee Health Science Center

874 Union Avenue, Memphis, TN 38163 E-mail: [email protected].

The University of Tennessee is an Equal Opportunity / Affirmative Action / Title VI / Title IX / Section 504 /

Americans With Disabilities Act / Age Discrimination in Employment Act Employer.

Research Asst. B Regular position available at Farber Institute for Neurosciences, Thomas Jefferson Univ. Requires MS and 4 year lab work experience. Able to anesthetize rats, do brain surgery in stereotaxic apparatus, transcardial perfusion and tissue extraction. Perform immunocytochemistry experiments including immunofluorescence, immunoperoxidase and immunogold labelings for electron microscopy. Expertise in EM, animal protocol compliance and lab operation mgt required. Send Resume to: Dr. Elisabeth Van Bockstaele, Farber Institute, 900 Walnut St, Ste. 417, Philadelphia, PA 19107

Postdoctoral Associatein

Computational Genomics of EukaryoticCells & Neuroinformatics

McKnight Brain Institute and Whitney Laboratoryof Marine BioscienceUniversity of Florida

We are seeking a computational biologist /bioinformatician to join an interdisciplinary team todevelop an integrated suite of neuroinformaticdatabases, tools, algorithms, languages, and standardsfocused on the biology of neurons, stem cells, andneuronal evolution. Our work in computational andcomparative neuroinformatics is directed at annotatingand characterizing the gene networks, signalingpathways and neuron specific genes required togenerate a computational model of a living neuron, onein which genomics, molecular, imaging, andphysiological data will be part of one integrated platform:The Portrait of a Living Neuron.˚ To apply, send acurriculum vitae and letters of recommendation to:

Peter A. Anderson, Ph.D.Professor and Director

Whitney Marine Laboratory of Marine BioscienceUniversity of Florida

9505 Oceanshore BoulevardSt. Augustine, FL 32080-9610˚

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