Synaptic plasticity in many different forms is widely recognized as essential to normal brain development, to homeostasis of the mature brain, and to our abilities to adapt to changing environments and injury and to learn. There is relatively little information, however, to link particular known forms of synaptic plasticity to particular forms or sites of behaviorally relevant brain circuit plasticity. This gap in our knowledge prevents us from efficiently pinpointing synapses of known functional relevance as we explore the molecular, synaptic, and circuit bases of memory and its disorders. The experiments proposed here will exploit unique advantages of the mouse whisker sensory system to explore basic mechanisms of neocortical synaptic plasticity. The work will apply a powerful new high-resolution proteomic imaging method called "array tomography" (AT) to measure molecular and structural characteristics of cortical synapse populations at the level of individual synapses. AT has unique abilities to resolve individual synapses in native circuit tissue context, to measure dozens of distinctive molecular markers (e.g., diverse receptor, transporter, signaling, scaffolding and adhesion proteins) at each synapse, and to do so with very high experimental throughput. Thus, AT can determine a high dimensional molecular signature for each individual synapse in very large populations and differentiate specific synapse subpopulations on the basis of such molecular signatures. The proposed research will develop and apply a novel AT-based screening strategy to search in an unbiased fashion for patterns of structural and molecular change occurring in specific mouse neocortical synapses in reaction to specific sensory adaptation and associative conditioning procedures.

Public Health Relevance

This research will apply a powerful new high-resolution proteomic imaging method called array tomography to pinpoint specific sites of synaptic plasticity associated with particular sensory adaptation and associative learning paradigms. The resulting new information on brain plasticity mechanisms will contribute to the development of improved drug treatments for neurodevelopmental and neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075252-03
Application #
8468763
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2011-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$466,449
Indirect Cost
$171,723
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Valenzuela, Ricardo A; Micheva, Kristina D; Kiraly, Marianna et al. (2016) Array tomography of physiologically-characterized CNS synapses. J Neurosci Methods 268:43-52
Micheva, Kristina D; Wolman, Dylan; Mensh, Brett D et al. (2016) A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. Elife 5:
Burette, Alain; Collman, Forrest; Micheva, Kristina D et al. (2015) Knowing a synapse when you see one. Front Neuroanat 9:100
Collman, Forrest; Buchanan, JoAnn; Phend, Kristen D et al. (2015) Mapping synapses by conjugate light-electron array tomography. J Neurosci 35:5792-807
PaÅŸca, Anca M; Sloan, Steven A; Clarke, Laura E et al. (2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12:671-8
Weiler, Nicholas C; Collman, Forrest; Vogelstein, Joshua T et al. (2014) Synaptic molecular imaging in spared and deprived columns of mouse barrel cortex with array tomography. Sci Data 1:140046
Wang, Gordon X; Smith, Stephen J; Mourrain, Philippe (2014) Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex. Neuron 84:1273-86
Busse, Brad; Smith, Stephen (2013) Automated analysis of a diverse synapse population. PLoS Comput Biol 9:e1002976
Burns, Randal; Roncal, William Gray; Kleissas, Dean et al. (2013) The Open Connectome Project Data Cluster: Scalable Analysis and Vision for High-Throughput Neuroscience. Sci Stat Database Manag :
Chung, Won-Suk; Clarke, Laura E; Wang, Gordon X et al. (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394-400

Showing the most recent 10 out of 19 publications