Remodeling of cortical networks by visual experience during development relies on rapid changes in synaptic structure and function. The exquisite specificity of these activity-driven synaptic changes begs the question of how they are implemented. Surprisingly we have recently shown that microglia, neuroimmune cells derived from bone marrow, may be critical in this process. Traditionally, microglia are considered to serve an exclusively immune function and exist in a quiescent state in the healthy brain. Instead, we posit that microglia are an integral part of brain circuitry and contribute critically o normal brain function and plasticity. Indeed, over the past two years we have shown that microglia dynamically contact synaptic elements (frequently surveilling the synaptic cleft), and that these microglial contacts result in alterations of synapse structure, a phenomenon linked to changes in synapse strength. Even more surprisingly, microglia discriminate different synaptic types and preferentially contact small, weak and transient structures, showing that interactions between microglia and synapses have remarkable specificity. Furthermore, visual deprivation leads to changes in these microglia- synapse interactions along with a striking increase in microglial phagocytosis, and phagocytic inclusions contain structures that strongly resemble synapses. Importantly, our preliminary data show that disruption of microglial function in the visual cortex attenuates visually-driven plasticity in vivo. Thus, our data suggest that microglia not only target synaptic subtypes and alter their structure, they actually remove unwanted synapses through a phagocytic process, all in an activity-dependent manner, and that this is a vital part of plasticity. These results are tantalizing and introduce a new way of thinking about mechanisms of activity-driven plasticity in the visual cortex that may also extend to other brain regions and functions. In this renewal application, we will examine how synaptic activity influences microglia-synapse interactions (Aim1). We will also explore the role of a putative molecular signal that could link activity at synapses with directed microglia-synapse interactions (Aim2). Lastly we will directly assay the contribution of microglia to functional plasticity and synaptic remodeling by acutely eliminating microglia from the visual cortex, as well as by altering microglial pathways involved in microglia-synapse communication (Aim3). The successful completion of these aims will determine the molecular mechanisms by which synapses interact with microglia, and establish microglial functions underlying neural plasticity. Because many neurodevelopmental and neurodegenerative disorders are characterized by synapse loss and neuroinflammation (microglial activation), accomplishing these aims will not only provide new mechanistic insights into brain plasticity but may also inform the development of treatment avenues for such diseases.

Public Health Relevance

Changes in the way neurons communicate are crucial to brain function, including development, learning, and aging, and defects in this neuronal plasticity underlie neurological disorders, such as autism, epilepsy and Alzheimer's disease. Here we introduce the novel notion that microglia, which are immune cells commonly thought to play a strictly immunosurveilance role in the healthy brain, are an integral part of brain circuitry and contribute critically to normal brain function and plasticity. Defining their role in the proposed experiments will yield 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 #
2R01EY019277-04A1
Application #
8434696
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Steinmetz, Michael A
Project Start
2009-01-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$383,750
Indirect Cost
$133,750
Name
University of Rochester
Department
Neurosciences
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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
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
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
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
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; 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
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
Majewska, Ania K (2013) Imaging visual cortical structure and function in vivo. J Glaucoma 22 Suppl 5:S21-3
Tremblay, Marie-Eve; Zettel, Martha L; Ison, James R et al. (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60:541-58

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