Peripheral B cell populations tune spontaneous neuronal activity in the uninjured hippocampus after stroke

B cells infiltrate the contralesional hippocampus following stroke, but whether lymphocytes modulate post-stroke plasticity and neuronal network function remains unknown. To identify immune cell mechanism(s) supporting remote plasticity, we examined the impact of B cell depletion on synaptic and neuronal activity in the hippocampal circuit following stroke. Basal synaptic transmission in the contralesional dentate gyrus (DG) following a stroke in adult male mice was decreased with B cell depletion. Expanding our studies to encompass the CA1 and DG regions of the hippocampal circuit in male and female mice of different ages, we utilized synapsin-Cre/GCaMP6s mice to visualize spontaneous calcium activity during a 3-week B cell depletion with and without prior stroke. Systemic B cell depletion in the absence of injury altered neuronal activity in the DG, suggesting a novel neuromodulatory role for circulating immune cells. Stroke increased Ca2+ transient amplitudes in the contralesional DG and CA1, with B cell depletion again reducing DG amplitudes while increasing the frequency of Ca2+ transients. Robust linear regression revealed significant main effects and higher-order interactions (depletionxsexxagexinjury), including increased Ca2+ transient amplitudes in older post-stroke mice lowered by systemic B cell depletion, though overall the DG appears more sensitive to modulation versus CA1. These results suggest that circulating B cells can tune hippocampal network activity dependent on age, sex, and the presence of brain injury. The selective vulnerability of the DG to depletion-age-injury interactions opens an avenue for future studies on region-specific neuroimmune crosstalk during post-stroke cognitive recovery. Presubmission inquiry for NeuronWe uncover crucial insights on the capacity of circulating B cells to directly modulate hippocampal network activity, showing that B cells are not just passive players, but active neuromodulators whose effects are dependent on sex, age, and stroke injury status. In fact, B cells are central players to functional recovery whose evolving role shifts over time, from acutely beneficial and neurotrophic to chronically maladaptive, depending on timing, context, and responding B cell subset. Our study demonstrates a mechanistic link between systemic immune modulation and neuronal calcium activity. This integrative perspective aligns with Neurons mission to publish studies that link cellular processes to systems-level functions. These novel findings also add to a more unified model of neuro-immune interactions that highlights how immunotherapies could be harnessed to improve neuronal function during stroke and aging, with several FDA-approved immunotherapeutics available to modulate systemic adaptive immune responses.