What enables a baby's brain to learn so rapidly during early developmental critical periods? What cell and molecular mechanisms cause the decline in extensive plasticity by adulthood? The goal here is to enhance synaptic plasticity by discovering and then blocking endogenous mechanisms that function to suppress plasticity and circuit change. Specifically, can manipulations of the neuronal receptor PirB (Paired Immunoglobulin-like receptor B;Lilrb3 in humans) "release the brake" on ocular dominance (OD) plasticity, a form of experience-dependent synaptic plasticity in visual cortex? In the immune system PirB is a receptor for Major Histocompatibility Class I molecules, famous ligands for T-cell receptors. This Lab made the unexpected discovery that neurons express PirB and MHCI molecules at synapses. OD plasticity is enhanced in visual cortex of mice with germline deletion of PirB, consistent with PirB acting to brake synaptic plasticity.
Three specific aims are proposed: 1) Determine if acute deletion of PirB postnatally enhances OD plasticity: A conditional allele of PirB (PirB flox/flox) has been made, allowing acute temporal and cell-type disruption of PirB by crossing mice with tamoxifen-inducible Cre transgenic lines. Direct blockade of PirB with recombinant soluble truncated PirB protein or function-blocking antibodies will also be used. These experiments should reveal when and in what cell types PirB acts. 2) Link enhanced OD plasticity in PirB-/- mice to cellular mechanisms of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) will be studied in vitro in visual cortex slices using physiological methods. Dendritic spine density of YFP-labeled layer 5 pyramidal neurons will be measured in PirB-/- vs WT mice reared with normal visual experience or with monocular eye closure;spine stability will be examined using two-photon microscopy. These experiments should broaden understanding of how PirB acts at synaptic and structural levels to suppress plasticity. 3) Identify PirB signal transduction pathways in mouse visual cortex: Candidate signaling pathways downstream of PirB will be identified and evaluated by comparing visually-driven signaling in WT vs germline PirB-/- mouse visual cortex during and after the critical period. Changes in expression and phosphorylation levels will be assessed in candidate pathways including MAP Kinase, AKT and mTOR signaling. Studies here will employ genetic, biochemical, electrophysiological, imaging and anatomical methods in mice to assess OD plasticity at the systems level and to understand cellular and molecular mechanisms of PirB function. Together, experiments should elucidate how PirB normally acts in neurons to suppress synaptic-plasticity signaling pathways during and beyond the critical period, as well as test feasibility of restoring OD plasticity by acute PirB blockade. They represent key steps in understanding mechanisms of developmental critical periods, as well as for designing new ways to enhance CNS function and repair by engaging the brain's inherent capacity for neural plasticity.
The idea that extensive synaptic plasticity might be restored to the brain by "releasing the brake" on mechanisms that act endogenously to suppress plasticity and circuit change has important clinical implications. If brain circuits can be restore to a more immature state in which synaptic plasticity can be easily engaged, it might be possible to facilitate recovery following damage or memory loss associated with Stroke, Alzheimer's or other neurodegenerative disorders of aging. Retraining the brain might also be applied post hoc for childhood learning disabilities including Dyslexia or Amblyopia in the developing visual system, and possibly even for treatment of Autism.
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