Remodeling of cortical networks in response to visual experience during development relies on specific and localized changes in synaptic structure and function, the progression and mechanisms of which are still poorly understood. While intracellular signaling has been the focus of most studies of the visual cortex, the extracellular environment plays a crucial role in limiting visual plasticity. We hypothesize that extracellular pathways, which are believed to be restricted to the injured or diseased brain, are surprisingly also active during plasticity in the visual cortex and allow structural remodeling at single synapses. Using imaging techniques which allow real time visualization of cellular morphology in vivo, we can, for the first time, visualize the rewiring of cortical networks during manipulations of vision at the level of a single synapse and directly examine entirely novel mechanisms of this rewiring. Using these methods, we will test the following scenario: monocular deprivation leads to extracellular protease activity resulting in microglial activation and extracellular matrix degradation, which in turn implement structural and functional plasticity.
In aim 1 we will quantify key aspects of this structural synaptic plasticity and determine its synaptic locus.
In aim 2, we will assay microglial involvement in visual plasticity and in aim 3 we will elucidate the extracellular pathway that leads to microglial activation and extracellular matrix remodeling. We will use a combination of in vivo functional and structural 4D imaging with histological, molecular and genetic tools which will provide unique insights into the extracellular mechanisms underlying plasticity in the visual cortex. Because of the broad range of morphological and functional synaptic deficits observed in neurodevelopmental and neurodegenerative disorders, accomplishing these aims will also provide insights into new treatment avenues for such diseases.

Public Health Relevance

The structure of synapses is crucial to the proper functioning of the nervous system: changes in this structure are observed during brain development, learning and in many neurological disorders, including autism, epilepsy and Alzheimer's disease. In this proposal we will study how synapse structure is modulated by natural stimuli in the intact brain and identify mechanisms mediating synaptic changes. This study will provide information with broad implications for understanding and treating a large spectrum of human neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019277-03
Application #
8123261
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Steinmetz, Michael A
Project Start
2009-08-01
Project End
2013-02-28
Budget Start
2011-08-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2011
Total Cost
$370,800
Indirect Cost
Name
University of Rochester
Department
Neurosciences
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Lowery, Rebecca L; Tremblay, Marie-Eve; Hopkins, Brittany E et al. (2017) The microglial fractalkine receptor is not required for activity-dependent plasticity in the mouse visual system. Glia 65:1744-1761
Sipe, G O; Lowery, R L; Tremblay, M-È et al. (2016) Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun 7:10905
Lantz, Crystal L; Sipe, Grayson O; Wong, Elissa L et al. (2015) Effects of Developmental Alcohol Exposure on Potentiation and Depression of Visual Cortex Responses. Alcohol Clin Exp Res 39:1434-42
Sullivan, Kelley D; Majewska, Ania K; Brown, Edward B (2015) Single- and two-photon fluorescence recovery after photobleaching. Cold Spring Harb Protoc 2015:pdb.top083519
Kelly, Emily A; Russo, Amanda S; Jackson, Cory D et al. (2015) Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice. Front Cell Neurosci 9:369
Kelly, Emily A; Opanashuk, Lisa A; Majewska, Ania K (2014) The effects of postnatal exposure to low-dose bisphenol-A on activity-dependent plasticity in the mouse sensory cortex. Front Neuroanat 8:117
Shapovalov, Yuriy; Zettel, Martha; Spielman, Sara C et al. (2014) Fluoxetine modulates breast cancer metastasis to the brain in a murine model. BMC Cancer 14:598
Lamantia, Cassandra; Tremblay, Marie-Eve; Majewska, Ania (2014) Characterization of the BAC Id3-enhanced green fluorescent protein transgenic mouse line for in vivo imaging of astrocytes. Neurophotonics 1:011014
Kelly, Emily A; Tremblay, Marie-Eve; Gahmberg, Carl G et al. (2014) Subcellular localization of intercellular adhesion molecule-5 (telencephalin) in the visual cortex is not developmentally regulated in the absence of matrix metalloproteinase-9. J Comp Neurol 522:676-88
Kelly, Emily A; Tremblay, Marie-Ève; Gahmberg, Carl G et al. (2013) Interactions between intercellular adhesion molecule-5 positive elements and their surroundings in the rodent visual cortex. Commun Integr Biol 6:e27315

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