Synaptic molecular imaging in spared and deprived columns of mouse barrel cortex with array tomography

A major question in neuroscience is how diverse subsets of synaptic connections in neural circuits are affected by experience dependent plasticity to form the basis for behavioral learning and memory. Differences in protein expression patterns at individual synapses could constitute a key to understanding both synaptic diversity and the effects of plasticity at different synapse populations. Our approach to this question leverages the immunohistochemical multiplexing capability of array tomography (ATomo) and the columnar organization of mouse barrel cortex to create a dataset comprising high resolution volumetric images of spared and deprived cortical whisker barrels stained for over a dozen synaptic molecules each. These dataset has been made available through the Open Connectome Project for interactive online viewing, and may also be downloaded for offline analysis using web, Matlab, and other interfaces.

[1]  David L. Hunt,et al.  Synaptic plasticity of NMDA receptors: mechanisms and functional implications , 2012, Current Opinion in Neurobiology.

[2]  D. Kleinfeld,et al.  'Where' and 'what' in the whisker sensorimotor system , 2008, Nature Reviews Neuroscience.

[3]  J. Garner,et al.  Barbering (fur and whisker trimming) by laboratory mice as a model of human trichotillomania and obsessive-compulsive spectrum disorders. , 2004, Comparative medicine.

[4]  K. Osen,et al.  The Vesicular GABA Transporter, VGAT, Localizes to Synaptic Vesicles in Sets of Glycinergic as Well as GABAergic Neurons , 1998, The Journal of Neuroscience.

[5]  Michael C. Crair,et al.  A critical period for long-term potentiation at thalamocortical synapses , 1995, Nature.

[6]  Mark Farrant,et al.  Differences in Synaptic GABAA Receptor Number Underlie Variation in GABA Mini Amplitude , 1997, Neuron.

[7]  D. Copenhagen,et al.  Vesicular Glutamate Transporters 1 and 2 Target to Functionally Distinct Synaptic Release Sites , 2004, Science.

[8]  Alison L. Barth,et al.  Pathway-Specific Trafficking of Native AMPARs by In Vivo Experience , 2006, Neuron.

[9]  Qian-Quan Sun,et al.  Experience-dependent intrinsic plasticity in interneurons of barrel cortex layer IV. , 2009, Journal of neurophysiology.

[10]  Thomas Boudier,et al.  TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organization , 2013, Bioinform..

[11]  C. Duarte,et al.  Regulation of AMPA receptors and synaptic plasticity , 2009, Neuroscience.

[12]  Karel Svoboda,et al.  Regular Spiking and Intrinsic Bursting Pyramidal Cells Show Orthogonal Forms of Experience-Dependent Plasticity in Layer V of Barrel Cortex , 2012, Neuron.

[13]  Michael P. Stryker,et al.  New Paradigm for Optical Imaging Temporally Encoded Maps of Intrinsic Signal , 2003, Neuron.

[14]  Claire E. J. Cheetham,et al.  Pansynaptic Enlargement at Adult Cortical Connections Strengthened by Experience , 2012, Cerebral cortex.

[15]  Jeanette Kotaleski,et al.  The Effects of NMDA Subunit Composition on Calcium Influx and Spike Timing-Dependent Plasticity in Striatal Medium Spiny Neurons , 2012, PLoS Comput. Biol..

[16]  J. Sanes,et al.  Chemoaffinity Revisited: Dscams, Protocadherins, and Neural Circuit Assembly , 2010, Cell.

[17]  Roberto Malinow,et al.  Synaptic AMPA Receptor Plasticity and Behavior , 2009, Neuron.

[18]  R. Sweet,et al.  Human Neuroscience , 2022 .

[19]  A. Lüthi,et al.  Experience-dependent changes in NMDA receptor composition at mature central synapses , 2007, Neuropharmacology.

[20]  M. Sassoè-Pognetto,et al.  Understanding the Molecular Diversity of GABAergic Synapses , 2011, Front. Cell. Neurosci..

[21]  Stephen J. Smith,et al.  Deep molecular diversity of mammalian synapses: why it matters and how to measure it , 2012, Nature Reviews Neuroscience.

[22]  P. Somogyi,et al.  Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  J. Fritschy,et al.  Is my antibody‐staining specific? How to deal with pitfalls of immunohistochemistry , 2008, The European journal of neuroscience.

[24]  Francisco Clascá,et al.  Mapping of fluorescent protein-expressing neurons and axon pathways in adult and developing Thy1-eYFP-H transgenic mice , 2010, Brain Research.

[25]  K. Svoboda,et al.  Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex , 2002, Nature.

[26]  K. Svoboda,et al.  Experience-dependent structural synaptic plasticity in the mammalian brain , 2009, Nature Reviews Neuroscience.

[27]  R. Malenka,et al.  AMPA receptor trafficking and synaptic plasticity. , 2002, Annual review of neuroscience.

[28]  D. Purpura,et al.  NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders , 2007, Nature Reviews Neuroscience.

[29]  Kristen M Harris,et al.  Ultrastructure of synapses in the mammalian brain. , 2012, Cold Spring Harbor perspectives in biology.

[30]  Stephen J. Smith,et al.  Sub-diffraction Limit Localization of Proteins in Volumetric Space Using Bayesian Restoration of Fluorescence Images from Ultrathin Specimens , 2012, PLoS Comput. Biol..

[31]  A Grinvald,et al.  In-vivo Optical Imaging of Cortical Architecture and Dynamics , 1999 .

[32]  Kristina D. Micheva,et al.  An anatomical substrate for experience-dependent plasticity of the rat barrel field cortex. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  K. Fox,et al.  Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex , 2008, Nature Neuroscience.

[34]  Kristina D. Micheva,et al.  Single-Synapse Analysis of a Diverse Synapse Population: Proteomic Imaging Methods and Markers , 2010, Neuron.

[35]  P. Somogyi,et al.  Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze‐fracture replica immunolabelling , 2010, The European journal of neuroscience.

[36]  P. McPherson Proteomic analysis of clathrin‐coated vesicles , 2010, Proteomics.

[37]  Stephen J. Smith,et al.  Array Tomography: A New Tool for Imaging the Molecular Architecture and Ultrastructure of Neural Circuits , 2007, Neuron.

[38]  Karel Svoboda,et al.  Rapid Redistribution of Synaptic PSD-95 in the Neocortex In Vivo , 2006, PLoS biology.

[39]  J. Storm-Mathisen,et al.  The Expression of Vesicular Glutamate Transporters Defines Two Classes of Excitatory Synapse , 2001, Neuron.

[40]  D. Feldman Synaptic mechanisms for plasticity in neocortex. , 2009, Annual review of neuroscience.

[41]  Karel Svoboda,et al.  Structural Plasticity Underlies Experience-Dependent Functional Plasticity of Cortical Circuits , 2010, The Journal of Neuroscience.

[42]  Robert A. Sweet,et al.  An automated segmentation methodology for quantifying immunoreactive puncta number and fluorescence intensity in tissue sections , 2008, Brain Research.

[43]  J. E. Vaughn,et al.  The fine structural localization of glutamate decarboxylase in synaptic terminals of rodent cerebellum. , 1974, Brain research.

[44]  Michael D. Ehlers,et al.  Metaplasticity at Single Glutamatergic Synapses , 2010, Neuron.

[45]  M. Bear,et al.  New views of Arc, a master regulator of synaptic plasticity , 2011, Nature Neuroscience.

[46]  M. Bear,et al.  Visual Experience and Deprivation Bidirectionally Modify the Composition and Function of NMDA Receptors in Visual Cortex , 2001, Neuron.

[47]  S. Hestrin,et al.  Electrical synapses define networks of neocortical GABAergic neurons , 2005, Trends in Neurosciences.

[48]  Helmut Grubmüller,et al.  Molecular Anatomy of a Trafficking Organelle , 2006, Cell.

[49]  G. Fishell,et al.  Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons , 2011, Developmental neurobiology.

[50]  Rebekah J. Corlew,et al.  Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex , 2005, The Journal of Neuroscience.

[51]  Array tomography: rodent brain fixation and embedding. , 2010, Cold Spring Harbor protocols.

[52]  Stephen J. Smith,et al.  Array tomography: production of arrays. , 2010, Cold Spring Harbor protocols.

[53]  H. Markram,et al.  Interneurons of the neocortical inhibitory system , 2004, Nature Reviews Neuroscience.

[54]  P. Stanton,et al.  Essential Role for Synaptopodin in Dendritic Spine Plasticity of the Developing Hippocampus , 2013, The Journal of Neuroscience.

[55]  D P Corey,et al.  Sound Amplification in the Inner Ear It Takes TM to Tango , 2000, Neuron.

[56]  R. Wong,et al.  A Comparison of Experience-Dependent Plasticity in the Visual and Somatosensory Systems , 2005, Neuron.

[57]  J. Lanciego,et al.  Expression of the mRNAs encoding for the vesicular glutamate transporters 1 and 2 in the rat thalamus , 2007, The Journal of comparative neurology.

[58]  M. Huntsman,et al.  Long-term sensory deprivation selectively rearranges functional inhibitory circuits in mouse barrel cortex , 2009, Proceedings of the National Academy of Sciences.

[59]  Peter Somogyi,et al.  Increased number of synaptic GABAA receptors underlies potentiation at hippocampal inhibitory synapses , 1998, Nature.

[60]  Qiang Zhou,et al.  NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease , 2013, Nature Reviews Neuroscience.

[61]  K. Fox,et al.  Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex , 2002, Neuroscience.

[62]  K. Fox,et al.  The Role of Cortical Activity in Experience-Dependent Potentiation and Depression of Sensory Responses in Rat Barrel Cortex , 2001, The Journal of Neuroscience.

[63]  M. Dalva,et al.  Cell adhesion molecules: signalling functions at the synapse , 2007, Nature Reviews Neuroscience.

[64]  F. Helmchen,et al.  Barrel cortex function , 2013, Progress in Neurobiology.

[65]  C. Bramham,et al.  The Arc of synaptic memory , 2009, Experimental Brain Research.

[66]  R. Huganir,et al.  Regulation of AMPA receptor trafficking and synaptic plasticity , 2012, Current Opinion in Neurobiology.

[67]  F. Helmchen,et al.  Microcircuit dynamics of map plasticity in barrel cortex , 2014, Current Opinion in Neurobiology.

[68]  Karel Svoboda,et al.  Experience-dependent and cell-type-specific spine growth in the neocortex , 2006, Nature.

[69]  Michael Brecht,et al.  Map Plasticity in Somatosensory Cortex , 2005, Science.

[70]  K. Rhodes,et al.  Antibodies as Valuable Neuroscience Research Tools versus Reagents of Mass Distraction , 2006, The Journal of Neuroscience.

[71]  T. Fuchs,et al.  GABAA Receptor Trafficking-Mediated Plasticity of Inhibitory Synapses , 2011, Neuron.

[72]  A. Holtmaat,et al.  Synapses Let Loose for a Change: Inhibitory Synapse Pruning throughout Experience-Dependent Cortical Plasticity , 2012, Neuron.

[73]  J. Storm-Mathisen,et al.  Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters , 2004, The Journal of comparative neurology.

[74]  R. Nicoll,et al.  Genetic analysis of neuronal ionotropic glutamate receptor subunits , 2011, The Journal of physiology.

[75]  Edward G Jones,et al.  Vesicular glutamate transporters define two sets of glutamatergic afferents to the somatosensory thalamus and two thalamocortical projections in the mouse , 2008, The Journal of comparative neurology.

[76]  H. Gainer,et al.  PSD-95 Is Required to Sustain the Molecular Organization of the Postsynaptic Density , 2011, The Journal of Neuroscience.

[77]  Roger A. Nicoll,et al.  Rapid Bidirectional Switching of Synaptic NMDA Receptors , 2007, Neuron.

[78]  David G. Lowe,et al.  Object recognition from local scale-invariant features , 1999, Proceedings of the Seventh IEEE International Conference on Computer Vision.

[79]  M. Schäfer,et al.  Homeostatic Scaling of Vesicular Glutamate and GABA Transporter Expression in Rat Neocortical Circuits , 2005, The Journal of Neuroscience.

[80]  C. Mulle,et al.  Presynaptic glutamate receptors: physiological functions and mechanisms of action , 2008, Nature Reviews Neuroscience.

[81]  M. Segal,et al.  The Spine Apparatus, Synaptopodin, and Dendritic Spine Plasticity , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[82]  Chris J. McBain,et al.  The Role of the GluR2 Subunit in AMPA Receptor Function and Synaptic Plasticity , 2007, Neuron.

[83]  F. Helmchen,et al.  Reorganization of cortical population activity imaged throughout long-term sensory deprivation , 2012, Nature Neuroscience.

[84]  D. Feldman,et al.  Inhibitory sharpening of receptive fields contributes to whisker map plasticity in rat somatosensory cortex. , 2005, Journal of neurophysiology.

[85]  S. Glazewski,et al.  Parvalbumin‐containing neurons, perineuronal nets and experience‐dependent plasticity in murine barrel cortex , 2009, The European journal of neuroscience.

[86]  Mark von Zastrow,et al.  Role of ampa receptor endocytosis in synaptic plasticity , 2001, Nature Reviews Neuroscience.

[87]  Benjamin D. Philpot,et al.  Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity , 2008, Neuropharmacology.

[88]  T. Wiesel,et al.  Functional architecture of cortex revealed by optical imaging of intrinsic signals , 1986, Nature.

[89]  Douglas J Slotta,et al.  Composition of the Synaptic PSD-95 Complex*S , 2007, Molecular & Cellular Proteomics.

[90]  Robert C. Bolles,et al.  Random sample consensus: a paradigm for model fitting with applications to image analysis and automated cartography , 1981, CACM.

[91]  I. Song,et al.  Regulation of AMPA receptors during synaptic plasticity , 2002, Trends in Neurosciences.

[92]  M. Sheng,et al.  Postsynaptic Signaling and Plasticity Mechanisms , 2002, Science.

[93]  E. P. Gardner,et al.  Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex , 2008, Nature Reviews Neuroscience.

[94]  John R Huguenard,et al.  Pathway-Specific Differences in Subunit Composition of Synaptic NMDA Receptors on Pyramidal Neurons in Neocortex , 2003, The Journal of Neuroscience.

[95]  S. Cull-Candy,et al.  Role of Distinct NMDA Receptor Subtypes at Central Synapses , 2004, Science's STKE.

[96]  Marcel Oberlaender,et al.  Sensory Experience Restructures Thalamocortical Axons during Adulthood , 2012, Neuron.

[97]  Array tomography: immunostaining and antibody elution. , 2010, Cold Spring Harbor protocols.

[98]  Taro Kiritani,et al.  Local-Circuit Phenotypes of Layer 5 Neurons in Motor-Frontal Cortex of YFP-H Mice , 2008, Frontiers in neural circuits.

[99]  S. Finkbeiner,et al.  Arc in synaptic plasticity: from gene to behavior , 2011, Trends in Neurosciences.

[100]  Xiaobing Chen,et al.  Organization of the core structure of the postsynaptic density , 2008, Proceedings of the National Academy of Sciences.

[101]  Jang-Yen Wu,et al.  A novel mechanism for GABA synthesis and packaging into synaptic vesicles , 2009, Neurochemistry International.

[102]  K. Sobue,et al.  Determination of absolute protein numbers in single synapses by a GFP-based calibration technique , 2005, Nature Methods.

[103]  Stephen Smith,et al.  Automated Analysis of a Diverse Synapse Population , 2013, PLoS Comput. Biol..

[104]  S. Grant,et al.  Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome , 2006, Journal of neurochemistry.

[105]  G. Feng,et al.  Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP , 2000, Neuron.

[106]  Gero Miesenböck,et al.  Experience-Dependent Rewiring of Specific Inhibitory Connections in Adult Neocortex , 2014, PLoS biology.

[107]  R. Huganir,et al.  Arc-dependent synapse-specific homeostatic plasticity , 2010, Proceedings of the National Academy of Sciences.

[108]  Kristina D. Micheva,et al.  Array tomography: high-resolution three-dimensional immunofluorescence. , 2010, Cold Spring Harbor protocols.

[109]  R. Galvez,et al.  Rapid adult experience-dependent anatomical plasticity in layer IV of primary somatosensory cortex , 2014, Brain Research.

[110]  K. Fox,et al.  The effect of vibrissa deprivation pattern on the form of plasticity induced in rat barrel cortex. , 1999, Somatosensory & motor research.

[111]  A. Cardona,et al.  Elastic volume reconstruction from series of ultra-thin microscopy sections , 2012, Nature Methods.

[112]  J. Fritschy,et al.  Epilepsy, E/I Balance and GABAA Receptor Plasticity , 2008, Frontiers in molecular neuroscience.

[113]  MB Kennedy,et al.  PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[114]  I. Módy Aspects of the homeostaic plasticity of GABAA receptor‐mediated inhibition , 2005, The Journal of physiology.

[115]  G. Köhr,et al.  NMDA receptor function: subunit composition versus spatial distribution , 2006, Cell and Tissue Research.

[116]  Mark F. Bear,et al.  Obligatory Role of NR2A for Metaplasticity in Visual Cortex , 2007, Neuron.

[117]  K. Fox,et al.  Sensory Deprivation Unmasks a PKA-Dependent Synaptic Plasticity Mechanism that Operates in Parallel with CaMKII , 2008, Neuron.