The major aim of this research is to learn how neural activity ultimately leads to synapse remodeling and circuit change in the developing mammalian visual system. A central question under study is, what happens in the brain during early critical periods of development? Answers are key to understanding causes of developmental neurological disorders such as Dyslexia and Autism. The hypothesis examined is that molecules and mechanisms not only enable, but also negatively regulate, synaptic plasticity in developing and adult visual system. Four interrelated Specific Aims focus on specific candidate molecules on both sides of the equation: 1) Determine if ocular dominance (OD) plasticity in mouse visual cortex requires MARK signaling during and after the critical period. A microarray screen identified a "common gene set" regulated by vision that are downstream targets of MARK. Experiments will block MARK function and examine consequences for OD plasticity. 2) Determine if SRF (Serum Response Factor) is required for OD plasticity. A conditional SRF knockout mouse will be used to examine whether SRF, a target of MARK, contributes to OD plasticity beyond, as well as during, the critical period. 3) Determine if PIRB, a novel immune receptor, limits the extent and/or duration of OD plasticity. We recently discovered that PIRB is expressed inCMS neurons. Preliminary studies in mutant mice lacking functional PIRB suggest that OD plasticity in visual cortex is enhanced. Experiments will characterize in detail visual system phenotypes of these mice in vivo. 4) Examine cellular mechanisms of synaptic plasticity in PIRB mutant mice. To establish mechanistic links between PIRB, synaptic plasticity and OD plasticity, and to gain physiological insight into PIRB function at synapses, whole cell microelectrode recordings will be made from neurons in slices of visual cortex or hippocampus. In all specific aims, OD plasticity will be assessed using tract tracing, optical imaging, and immediate early gene induction methods;molecular and biochemical techniques, as well as in situ hybridization, will be used to monitor levels and patterns of gene expression and function. An important implication of these proposed studies is that cortical circuits may retain substantial ability to undergo synaptic change even in adulthood. Thus, if negative regulators of plasticity such as PIRB are present, new therapies may be available for treating developmental learning disorders, as well as adult cognitive loss and stroke.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002858-35
Application #
8004984
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Steinmetz, Michael A
Project Start
1979-01-01
Project End
2012-08-31
Budget Start
2011-01-01
Budget End
2012-08-31
Support Year
35
Fiscal Year
2011
Total Cost
$571,325
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Adelson, Jaimie D; Sapp, Richard W; Brott, Barbara K et al. (2016) Developmental Sculpting of Intracortical Circuits by MHC Class I H2-Db and H2-Kb. Cereb Cortex 26:1453-63
Bochner, David N; Sapp, Richard W; Adelson, Jaimie D et al. (2014) Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia. Sci Transl Med 6:258ra140
Lee, Hanmi; Brott, Barbara K; Kirkby, Lowry A et al. (2014) Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509:195-200
Djurisic, Maja; Vidal, George S; Mann, Miriam et al. (2013) PirB regulates a structural substrate for cortical plasticity. Proc Natl Acad Sci U S A 110:20771-6
Kim, Taeho; Vidal, George S; Djurisic, Maja et al. (2013) Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341:1399-404
Adelson, Jaimie D; Barreto, George E; Xu, Lijun et al. (2012) Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73:1100-7
William, Christopher M; Andermann, Mark L; Goldey, Glenn J et al. (2012) Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice. J Neurosci 32:8004-11
Kanold, Patrick O; Kim, Yoon A; GrandPre, Tadzia et al. (2009) Co-regulation of ocular dominance plasticity and NMDA receptor subunit expression in glutamic acid decarboxylase-65 knock-out mice. J Physiol 587:2857-67
Datwani, Akash; McConnell, Michael J; Kanold, Patrick O et al. (2009) Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron 64:463-70
McKellar, Claire E; Shatz, Carla J (2009) Synaptogenesis in purified cortical subplate neurons. Cereb Cortex 19:1723-37

Showing the most recent 10 out of 71 publications