Neuroinflammatory Modulation of Synaptic Plasticity: Unraveling Glia–Neuron Crosstalk through Multi-Scale Molecular Profiling

Synaptic plasticity forms the cellular foundation of learning and memory, yet its regulation under neuroinflammatory conditions remains incompletely understood. Growing evidence suggests that immune-derived cytokines dynamically influence neuronal structure and function through bidirectional communication between glial and neuronal networks.

In this study, we sought to elucidate the molecular architecture of glia–neuron crosstalk that shapes synaptic remodeling during inflammation. Using human cortical organoids and murine hippocampal slice cultures, we induced controlled inflammatory states via interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) exposure. We employed single-cell RNA sequencing, quantitative proteomics, and super-resolution imaging to map cell-type-specific transcriptional and structural responses. Gene-regulatory network reconstruction identified a cascade centered on NF-κB, complement C3, and PGC-1α, linking immune activation to metabolic reprogramming and synaptic pruning.

Functional validation using CRISPR interference and pharmacological inhibition confirmed that NF-κB blockade restored dendritic spine density, enhanced long-term potentiation (LTP), and rescued mitochondrial integrity. Conversely, astrocytic overexpression of C3 exacerbated synaptic loss, demonstrating a direct glial contribution to excitatory circuit instability. Mitochondrial respiration assays further revealed that inflammatory signaling suppresses oxidative phosphorylation while increasing glycolytic flux, coupling energy dysregulation with synaptic impairment.

Collectively, these data delineate a multi-layered signaling network whereby neuroinflammation modulates synaptic plasticity through transcriptional, metabolic, and structural mechanisms. Targeting the NF-κB–PGC-1α axis and glial complement pathways may therefore offer new strategies to restore circuit homeostasis in neurodegenerative and psychiatric disorders.