BDNF-Producing B Cells Mediate Plasticity in the Recovering Brain After Stroke

Neuronal networks require significant neurotrophic support for functional plasticity after stroke, but the delivery of neurotrophins has failed thus far in clinical trials. Therefore, identifying endogenous mechanisms that could enhance neurotrophic support in the recovering brain after stroke is essential. B cells, a lymphocyte known to infiltrate the post-stroke brain, possess the ability to produce neurotrophins, including brain-derived neurotrophic factor (BDNF). Depleting B cells after stroke results in motor and cognitive deficits that are mediated by specific brain regions (e.g., hippocampus) outside the initial infarct. We propose that B cells migrate to specific brain regions after stroke and respond to local signals that enhance their neurotrophic capacities to promote neuroplasticity. To investigate whether B cells are a potential source of endogenous BDNF support after stroke, we must identify 1.) the spatial distribution of B cells within the post-stroke brain, 2.) the type of neurotrophic support B cells provide to ischemic-injured neurons and 3.) the impact that the post-stroke microenvironment exerts on the neurotrophic capacity of B cells. Using whole brain microscopy, we discovered that B cells migrate to specific remote brain regions areas outside of the initial infarct that regulate motor and cognitive function after stroke. To understand how B cells support ischemic-injured neurons, we used ex vivo electrophysiology and in vitro models of ischemic injury to assess functional and structural neuroplasticity in the presence or absence of B cells. We discovered that B cells support synaptic transmission in the dentate gyrus region of the hippocampus after stroke and through the production of BDNF, B cells protect against the ischemic-induced loss of neurons and neuronal dendrites. After stroke, neuronal BDNF production is dependent on glutamate-induced activity of the N-methyl-D-aspartate receptor (NMDAR) downstream of the GluN2A subunit. Given that B cells also express NMDARs, we investigated whether glutamate can similarly upregulate BDNF in B cells downstream of their NMDARs. Using microscopy, flow cytometry and qPCR, we discovered that stroke and glutamate differentially regulate B cell gene and surface expression of GluN2A. Additionally, both mouse and human B cells elicit a functional response to glutamate and can induce autocrine BDNF signaling. Collectively, the data presented in this thesis are the first to demonstrate a glutamate-induced neurotrophic role for B cells in the ischemic brain. Understanding the mechanisms by which neuroinflammation supports neuroplasticity after stroke enables the development of immune-based therapeutics that harness endogenous neurotrophic support from B cells to ameliorate pathology.