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    823—Striate Cortex: Ocular Dominance Plasticity

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    823.09: Acute enhancement of plasticity and spine density by blockade of PirB

    Location: Halls B-H

    ">*D. N. BOCHNER1, R. W. SAPP2, G. S. VIDAL1, M. DJURISIC2, C. J. SHATZ2;
    1Neurosciences PhD Program, 2Biol. and Neurobio., Stanford Univ., Stanford, CA

    Abstract Body: Over the life of an animal, activity-dependent plasticity is dynamically regulated, high levels of plasticity present during developmental critical periods and decreasing as the animal ages. Recently, negative regulators have been identified which, when present, limit the amount of available plasticity, including Paired Immunoglobulin-like Receptor B (PirB) and its ligand Major Histocompatibility Class I (MHCI). Here we show that local, specific pharmacological blockade of PirB function can acutely enhance plasticity during and even after the ODP critical period.
    We generated a soluble form of PirB (sPirB) containing the PirB ectodomain plus tags for detection and purification, and infused either sPirB or control solution for 10 days into V1 of WT mice using osmotic minipumps. ODP was induced by monocular enucleation (ME) and was assessed by measuring the expansion of the open eye representation in layer 4 of visual cortex. When WT mice are implanted with minipumps shortly before critical period ME (P28-32), mice infused with sPirB have 24% greater expansion than controls (p<0.0001). In adult WT mice with ME (P70-74), minipump infusion of sPirB results in a 12.5% enhancement of open-eye expansion compared to controls (p=0.0015). This effect is lost when sPirB is infused into visual cortex of adult PirBKO mice, suggesting that the manipulation is PirB-specific. Enhanced ODP has been correlated structurally with increased spine density on apical dendrites of L5 pyramidal neurons. Therefore we assessed spine density following infusions of sPirB or control into WT YFP-H mice. The density of apical dendritic spines is increased in mice infused with sPirB (sPirB: 0.54 vs control: 0.39 spines/µm, p=0.0019). This increase is also present on basolateral dendrites (sPirB: 0.60 vs control: 0.43 spines/µm; p=0.0047). This significant and acute increase in spine density may explain the enhancement of OD plasticity after sPirB infusion by providing a structural substrate for more rapid synaptic change. Our results show that PirB not only “brakes” ODP, but also spine density, which can be rapidly increased even in adulthood using a dominant negative PirB receptor. Together, results imply that PirB is a target throughout life for interventions that enhance plasticity for the purposes of learning, recovery from injury, or disease states.

    Lay Language Summary: Neuroscientists have long dreamed of leveraging the brain’s ability to change its connections with experience, often referred to as neural plasticity, to facilitate recovery from injury, learning disabilities or neurodegeneration. Our research has found molecules in the brain that act as brakes throughout life to limit neural plasticity. By targeting these molecules with blockers, it is possible to make the brain more plastic, even when it wouldn’t normally be receptive to new experiences.
    Neural plasticity—changing neural connections to make new memories, learn new skills, or recover from an injury—is one of the brain’s most amazing capabilities. But as anyone who’s tried to learn a second language after age 13 or so knows, sometimes it’s harder to get the brain to change. There are time windows, called critical periods, when the brain is more plastic. After a critical period ends, it’s much harder to coax the brain to change. Our lab studies molecules that limit plasticity, so that we could temporarily “let up on the brakes” and make the brain better at learning and repairing itself later in life.
    Language learning isn’t the only developmental process with a critical period. For the visual system to become properly wired, both eyes must be able to see early in life. In mice, there are distinct parts of the brain that process information from each eye, with a small binocular region that responds to both eyes. If one eye can’t see during the first month of a mouse’s life (or two years for a human) the region corresponding to the spared eye takes over territory in the brain that should have belonged to the closed eye, a process called ocular dominance plasticity. But if the eye is closed after the end of the critical period, there is little or no effect on the structure of the visual system. Ocular dominance plasticity is used as a model for how neural circuits change themselves in response to changing experience.
    Our lab discovered a gene, called PirB, which acts as a brake on brain plasticity. Mice lacking this gene show more expansion of open-eye brain territory than genetically normal mice when an eye is closed. So we tested whether we could target PirB to enhance brain plasticity at any time during the animals’ life.
    We engineered a molecule that blocks the animal’s own PirB from functioning by luring away PirB’s normal binding partners, and then infused either this molecule or a control solution into mouse brains. In adult mice, after the critical period, there usually isn’t any expansion of open-eye brain territory with prolonged eye closure. But infusing our “decoy” for ten days made the brain plastic enough for the open-eye territory to expand, bringing back a measure of plasticity that these mice had when they were younger.
    Even in young mice, infusing our PirB blocker also increases the amount of open-eye expansion, suggesting that PirB also works to limit neurological change early in life, when the brain is already fairly plastic. Since these brakes make it harder for experience to alter circuits during critical periods, they may exist to prevent plasticity from going haywire. After all, it wouldn’t be helpful to learn languages at super-speed if you kept forgetting them at the same rate!
    We hope to one day use drugs that disrupt PirB and related molecules as a means to temporarily increase brain plasticity in humans, promoting recovery after injury, treating neurological disorders, or just helping 50 year old people learn a language as easily as they could when they were 5.