Experience-driven plasticity in cortex regulated by neuronal PirB receptor [electronic resource]

Learning and memory require synaptic plasticity that is driven by neuronal activity. Neuronal molecules can control the stability and plasticity of cortical circuits, and understanding precisely how, when, and where they are needed to control these circuits forms a basis for developing therapeutics that could enhance plasticity after brain disease or injury. This dissertation explores how Paired Immunoglobulin-like Receptor B (PirB; human homologue is LilrB2), a receptor expressed by mouse cortical neurons regulates rules for activity-dependent synaptic plasticity, as well as an anatomical substrate for cortical plasticity. Moreover, PirB can bind to amyloid beta, leading to synaptic depression early on during Alzheimer's disease. Finally, I demonstrate that PirB acts in a cell-autonomous manner within excitatory pyramidal neurons of the cerebral cortex. In Chapter One, I introduce the visual system in mice as an elegant and practical model for understanding molecular mechanisms for cortical plasticity, as well as a current review of the prevalent hypotheses surrounding the topic. In Chapter Two, I show that PirB controls a threshold for visual cortical plasticity by regulating the density of dendritic spines, and also by regulating the balance of long-term potentiation (LTP) and long term depression (LTD) at cortical synapses. Specifically, PirB−/− mice have greater dendritic spine density along layer V apical dendrites, and these spines are less motile in vivo and in slice, suggesting that they may act as a more stable substrate for plasticity. PirB−/− mice also have enhanced LTP and deficient LTD (layer IV to II/III), indicating a shift in Hebbian plasticity thresholds. The the frequency of mEPSCs is also greater than in wild type (WT) in both layer V and layer II/III pyramidal neurons of visual cortex.. Together, these results suggest that PirB is required for regulating the structural stability of individual spines, regulating LTP/LTD thresholds, and restricting functional synapse number in multiple layers of visual cortex. Results presented in this chapter were published: Djurisic M, Vidal GS, Mann M, Aharon A, Kim T, Ferrao Santos A, Zuo Y, Hübener M, Shatz CJ (2013). PirB regulates a structural substrate for cortical plasticity. PNAS 110:20771-6. In Chapter Three, I present evidence that PirB and its human homologue LilrB2 can bind to oligomeric forms of amyloid beta, and demonstrate that APP/PS1 transgenic mice have excessive LTD in visual cortex well before they suffer cognitive decline. In contrast, PirB−/− mice carrying the APP/PS1 transgene have normal levels of LTD and do not experience memory loss at ages when the APP/PS1 transgenic mice do. Furthermore, I find that application of soluble oligomeric amyloid beta to WT hippocampal slices generates the expected defect in LTP, but LTP is intact in the presence of Aβ oligomers in PirB−/− hippocampus. These results suggest that PirB contributes to the well-known oligomeric amyloid beta-induced pathology, including memory loss and altering LTP/LTD thresholds in hippocampus and visual cortex, in both juveniles and adults. Results in this chapter were published: Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (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. In Chapter Four, I explore the question of where PirB acts to regulate spine and synapse density. I show that PirB−/− mice have greater spine density on the dendrites of layer II/III pyramidal neurons in juvenile visual cortex, and that cell-specific knockout of PirB just in layer II/III pyramidal neurons elevates spine density without affecting other aspects of neuronal morphology, such as dendritic arborisation. Moreover, by deleting PirB in just a small subset of neurons to create a mosaic of PirB−/− neurons surrounded by many more WT neurons, I find that there is a spine density increase on the PirB−/− neurons compared to neighbouring WT neurons, and that PirB−/− neurons have greater frequency (but not amplitude) of miniature EPSCs. These results suggest that layer II/III cortical neurons require PirB to regulate spine density, and that PirB regulates excitatory synaptic connectivity in a cell-autonomous manner during a developmental critical period of the cortex. These experiments suggest that PirB regulates LTP and LTD thresholds as well as the stability and density of dendritic spines and functional synapses in multiple layers of visual cortex. Furthermore, this regulation is shifted toward excessive pruning and synapse loss when binding to oligomeric amyloid beta, such as during Alzheimer's disease. Finally, in mosaic experiments, I discovered that PirB can act to prune dendritic spines, as well as to eliminate functional synapses in a cell-autonomous manner. Thus, PirB is a fundamental regulator of synaptic plasticity in cerebral cortex.

Advisor: Shatz Carla J. primary advisor. Thesis advisor
Madison Daniel V.
McConnell Susan K. advisor. Thesis advisor
Zuo Yi