CX3CL1-CX3CR1 signaling shapes the sex- and region-dependent neuroimmune response to LPS: Impact on plasticity and kynurenine pathway metabolism in the hippocampus.

BACKGROUND: Fractalkine signaling is a central mediator of neuron-microglia communication. We previously demonstrated that, under physiological conditions, the fractalkine receptor (CX3CR1) differentially modulates synaptic plasticity along the dorsoventral axis of the hippocampus in male but not in female mice. During systemic inflammation, CX3CR1 deficiency has been associated with altered regulation of the kynurenine pathway (KP), a metabolic route whose neuromodulatory metabolites show sex-dependent differences. However, it remains unclear how acute systemic inflammation affects synaptic plasticity and KP metabolism in the dorsal (DH) and ventral hippocampus (VH), whether these responses differ between sexes, and to what extent they depend on CX3CR1. METHODS: Acute systemic inflammation was induced via intraperitoneal injection of lipopolysaccharide (LPS) in male and female C57BL/6J and Cx3cr1-/- mice. Long-term potentiation (LTP) was assessed at 3 and 24 h post LPS treatment in DH and VH slices using extracellular field recordings. KP metabolites were quantified at 24 h by HPLC-ESI-MS/MS. RESULTS: In C57BL/6J males, LPS elicited a time- and region-specific modulation of plasticity, with early LTP suppression in the DH and delayed enhancement in the VH, accompanied by robust KP activation. In Cx3cr1-/- males, the KP activation and the dorsoventral pattern were altered, indicating that CX3CR1 is required for coordinated hippocampal neuroimmune responses during inflammation. In C57BL/6J females, LPS induced a modest enhancement of VH LTP together with a comparatively attenuated KP response, whereas Cx3cr1-/- females showed selective VH LTP impairment and reduced KP activation, suggesting that CX3CR1 signaling preserves VH plasticity during inflammatory challenge in females. CONCLUSIONS: Together, our findings identify fractalkine signaling as a key modulator of hippocampal synaptic plasticity and neuroimmune-metabolic responses to inflammation in a sex- and region-dependent manner.