Reelin regulation of the crosstalk between the Immune and Nervous systems

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The brain and immune system readily respond to multiple internal and external signals and adapt and change with these experiences. In addition, the immune system and the brain clearly influence each other, and this crosstalk also has an effect in their plasticity and behavior. My general research program focuses on studying the mechanisms underlying immune and neural plasticity, and how these mechanisms affect the brain and immune system functions and the interactions between both systems. In this proposal, I will evaluate the hypothesis that reelin, an extracellular matrix protein expressed both in brain and blood plasma, plays an important role in regulating immune and neural plasticity and in facilitating the crosstalk between both systems. Reelin was first identified as a critical protein in brain development, and thereafter it was shown to regulate neural plasticity and the interaction between GABAergic and glutamatergic systems in the adult brain. In addition to the brain, reelin is also expressed in blood plasma and lymphatic cells, and animals with reelin deficiencies appear to show prominent alterations in their immune system. However, there has been no systematic investigation of how reelin influences the immune system or the crosstalk between the brain and the immune system. My recent work has begun to address this issue. We have shown that glucocorticoids affect reelin expression in specific brain regions and also that reelin deficits bring about alterations in membrane protein clustering in blood lymphocytes. To directly assess the potential role of reelin in regulating neural and immune crosstalk, I propose a series of experiments designed to analyze the effects of reelin downregulation on the expression and membrane clustering of neurotransmitter receptors and transporters located both in brain and the immune system, and on the release of cytokines (particularly on cytokines that are observed both in the brain and periphery). In the case of the in vivo system, I will also study alterations in cognitive behavior associated with reelin deficits (i.e. object recognition test). I also propose to administer recombinant reelin to animals where a reelin deficit has been induced either genetically or through the application of glucocorticoids. In this case, I plan to assess whether the administration of recombinant reelin can restore the alterations in brain and immune plasticity and also on behavior, that we expect to see in reelin-deficit animals.